Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Desidustat Oral Tablet in Sickle Cell Disease: A Phase IIa Proof-of-Concept Evaluation

Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Desidustat Oral Tablet in Sickle Cell Disease: A Phase IIa Proof-of-Concept Evaluation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Desidustat Oral Tablet in Sickle Cell Disease: A Phase IIa Proof-of-Concept Evaluation Mayank Gangwar, Gunjan Kumar, Sudipto Roy, Sanjeev Gupta, Deven P Parmar, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6911159/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background: Sickle cell disease (SCD) is a genetic disorder characterized by chronic hemolysis and vaso-occlusive crises. Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), has shown promise in treating SCD by stimulating erythropoietin production in a similar manner that happens in response to hypoxia, promoting erythropoiesis and improving iron metabolism leading to increased hemoglobin and RBC indices. Methods: This is a Phase IIa, double-blind, randomized, placebo-controlled, parallel-group, proof-of-concept, multicenter clinical trial designed to evaluate the efficacy and safety of Desidustat in Indian adults with sickle cell disease (SCD). A total of 24 participants will be enrolled based on predefined eligibility criteria, with 8 subjects per dose cohort (50 mg, 100 mg and 150 mg), randomized in a 3:1 ratio (Desidustat: Placebo). The study includes a screening period of up to 4 weeks, an 8-week treatment phase, and a follow-up visit at Week 10, totaling 98 days. Efficacy (hemoglobin response rate) will be assessed at Week 8 relative to baseline compared to placebo. Dose adjustment of Desidustat at week 4 will be guided by hemoglobin levels measured using a calibrated HemoCue instrument. Discussion: Management of sickle cell disease (SCD) has limited treatment modalities available like hydroxyurea and blood transfusions. They offer benefits but their limitations underscore the ongoing need for safer, more effective, and accessible treatments. This proof-of-concept trial will investigate the efficacy and, safety of Desidustat oral tablet, 3 times per week for 08 weeks in SCD patients. Results from this trial could aid in establishing a cost-efficient therapeutic option for managing rare disease like SCD. Trial registration: The study is approved and is being conducted for new drug as per the GCP guideline of Central Drugs Standard Control Organization (CDSCO), CT NOC number is CT/SND/27/2023 with protocol number DESI.23.001, Version No. 01 Registered on 12 June 2023. Rare Disease Desidustat Hemoglobin Sickle cell disease HIF-PHI Figures Figure 1 Figure 2 Figure 3 Introduction Background and rationale {6a} Sickle cell disease (SCD) is a hereditary hemoglobinopathy caused by a single point mutation (GAG to GTG) in the β-globin gene, resulting in the substitution of glutamic acid with valine at position six (βGlu6Val) [1]. This mutation leads to the production of hemoglobin S (HbS), which polymerizes under deoxygenated conditions, distorting red blood cells (RBCs) into a sickled shape. These sickled RBCs are rigid and adhesive, leading to microvascular occlusion, recurrent vaso-occlusive crises (VOCs), chronic hemolytic anemia, and progressive multi-organ damage. The lifespan of sickled RBCs is significantly reduced (approximately 16 days) compared to normal RBCs (approximately 120 days), contributing to the chronic anemia observed in SCD patients. The pathophysiology of SCD involves a complex interplay of four interrelated processes: HbS polymerization, impaired blood flow and vaso-occlusion, hemolysis-mediated endothelial dysfunction, and sterile inflammation triggered by innate immune pathways. These mechanisms collectively result in acute and chronic complications such as pain crises, stroke, acute chest syndrome, and organ failure [2]. Current treatment strategies primarily focus on symptom management and reduction of disease severity, but curative approaches such as hematopoietic stem cell transplantation are limited by donor availability and associated risks. Hydroxyurea (HU), the first FDA-approved disease-modifying therapy for SCD, exerts its benefits primarily by inducing fetal hemoglobin (HbF) production, which inhibits HbS polymerization. However, HU has limitations including variable efficacy, poor adherence, and myelosuppressive side effects [3, 4]. In 2019, crizanlizumab, an anti-P-selectin monoclonal antibody, was approved by USFDA to reduce the frequency of vaso-occlusive crises (VOCs) [5]. However, SCD remains a disease with considerable unmet clinical need. Desidustat, a novel hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) inhibitor, offers a promising approach for SCD by pharmacologically stimulating erythropoiesis through activation of the HIF pathway. This mechanism mimics the physiological response to hypoxia, increasing endogenous erythropoietin (EPO) production and supporting red blood cell production. Desidustat has demonstrated efficacy and safety in Phase I–III trials for treating anemia in chronic kidney disease (CKD) patients, both on dialysis and not on dialysis and has got marketing approval in India in March-2022 [6]. In vitro studies have shown that Desidustat can reduce sodium metabisulfite-induced sickling in RBCs from SCD patients, suggesting potential disease-modifying activity. Preclinical studies further support its safety, bioavailability, and hematopoietic efficacy across various animal models. Desidustat exhibited minimal genotoxicity and no significant adverse effects on reproductive parameters in animal studies [7]. Clinically, Desidustat was well tolerated up to 300 mg in Phase I trials [8] and showed a dose-dependent increase in hemoglobin levels in CKD patients during subsequent Phase II and III studies, with no serious adverse events or persistent lab abnormalities reported [9]. Given this encouraging evidence, a Phase IIa proof-of-concept clinical trial has been designed to evaluate the safety and efficacy of Desidustat in adults with SCD. The trial involves administration of Desidustat oral tablets (50, 100, or 150 mg) three times per week over an eight-week period to assess changes in hemoglobin level while monitoring adverse effects. This trial aims to prove the potential of desidustat as a novel, orally administered therapy that could address the limitations of current treatments, such as hydroxyurea and blood transfusions with a mechanism that complements and potentially surpasses existing therapies. Desidustat has the potential to be an integral part of SCD management, improving patient outcomes, quality of life and cost-effectiveness. Objectives {7} The purpose of this study is to evaluate the efficacy and safety of Desidustat oral tablet three times per week for 08 weeks in sickle cell disease patients comapred to placebo. Trial Design {8} This is a multicenter, Phase IIa, randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept clinical trial evaluating the efficacy and safety of Desidustat in adult Indian patients with SCD. A total of 24 participants will be enrolled and randomized into three dose cohorts (50 mg, 100 mg, and 150 mg), each including 6 participants receiving Desidustat and 2 receiving placebo, administered orally three times a week for 8 weeks. Interim blinded safety data from the first 12 participants will be reviewed by an independent Data Safety Monitoring Board (DSMB). Efficacy will be assessed by change in hemoglobin levels and other hematologic parameters. Safety evaluations include adverse event monitoring, physical examination, vital signs, ECG, echocardiography, and laboratory assessments. Methods: Participants, interventions and outcomes Study setting {9} The study will be conducted across 5 centers in India (2 private multispecialty hospitals and 2 academic hospitals, 1 government hospital). The list of trial sites can be found on Clinical Trial Registry- India website. Eligibility criteria {10} Inclusion criteria: · Adults aged ≥18 years. · Indian male or female with confirmed sickle cell disease (any genotype) by laboratory evidence (e.g., hemoglobin electrophoresis, HPLC, or genetic testing). · Hemoglobin: 7–11 g/dL for males; 6.5–11 g/dL for females. · At least 1 episode of documented vaso-occlusive crisis (VOC) in the past 12 months. · Serum ferritin ≥100 ng/mL and/or transferrin saturation (TSAT) ≥20% at screening. · No significant vitamin B12 or folate deficiency. · Stable dose of hydroxyurea, L-glutamine, or crizanlizumab (if applicable) for ≥60 days before consent. · Agreement to use adequate contraception during the study and for 30 days after the last dose. · Signed informed consent (or thumb impression with impartial witness for illiterate participants). Exclusion Criteria · Recent blood transfusion (<30 days), hospitalization for VOC (<14 days), or participation in another clinical trial (<3 months). · Current treatment with Voxelotor, erythropoietin, or hematopoietic growth factors. · Significant lab abnormalities (e.g., low neutrophils ≤ 1.5 x 10 3 /µL or platelets ≤ 100 x 10 3 /µL, high bilirubin >3.5 mg/dL or ALT ≥ 2.5 times ULN). · For diabetic patients, HbA1c > 9 g/dL. · History of chronic inflammatory disease, systemic disorders or diseases, stroke or intracranial hemorrhage, cirrhosis, severe renal dysfunction or on chronic dialysis, thrombosis, or pancreatitis/MI within 6 months. · History of severe allergic or hypersensitivity reaction to investigational products and its excipients. · Presence or a history of bleeding disorders or clinical conditions · Active infections (e.g., HIV, Hepatitis A/B/C, malaria), or recent IV antibiotic or iron treatment (within 14 days prior to enrolment). · Medical conditions compromising safety (e.g., cardiovascular disease, bleeding disorders, malignancy, uncontrolled diabetes, inflammatory diseases). · Any major surgery within 90 days prior to randomization, and minor surgery within 30 days prior to randomization · Pregnancy, lactation, or inadequate birth control in women of childbearing potential. · Substance abuse, smoking/tobacco >10/day, or difficulty donating blood. · Clinically significant ECG, echocardiogram, or systemic disorders. · Need for anticoagulation therapy that may pose safety risks. · Investigator-determined conditions that may affect safety or data integrity. Who will take informed consent? {26a} Written Informed consent will be taken by Principal investigator/designee in this trial. For illiterate participants, the consent process will involve a verbal explanation in a language understood by the participant, a thumb impression, and the signature of an impartial witness. Participants will receive a copy of the signed consent form. Additional consent provisions for collection and use of participant data and biological specimen in ancillary studies, if applicable? {26b} Not applicable Interventions Explanation for the choice of comparators {6b} The dose regimen of 50, 100 mg and 150 mg Desidustat tablets three times a week for oral administration along with matching placebo have been selected to assess the therapeutic effect, safety of the drug and dose optimization for future clinical development. The doses have been selected based on previous clinical trials conducted. Intervention description {11a} Participants in the study will be randomly assigned to receive either Desidustat or placebo in one of three treatment cohorts (Figure 1). The study drug will be administered three times per week for a duration of eight weeks, with at least 48 hours between doses. Participants in the treatment arm will receive 50 mg, 100 mg, or 150 mg doses of Desidustat, with 150 mg dose provided as a combination of available strengths (50 mg, 100 mg). The placebo group will follow the same schedule using matching placebo. Study drugs are packaged, labelled, and supplied by the sponsor in accordance with regulatory requirements. The investigator is responsible for confirming receipt and maintaining accurate records of IP inventory, dispensing, and return. Investigational products are being stored securely at the site and returned to the sponsor or destroyed as per protocol following drug accountability procedures. All study medications are being stored at temperatures below 30°C, and appropriate temperature logs are being maintained. Participants will be advised not to consume any food 1 hour before and 2 hours after the administration of study drug. Criteria for discontinuing or modifying allocated interventions {11b} Dose modifications will be performed at week 4 based on changes in hemoglobin (Hb) levels compared to baseline. The target is to maintain Hb levels below 12 g/dL. Hb is being measured using a calibrated HemoCue device at week-4, taking the average of two readings, from EDTA or fresh blood samples. Dose adjustments will follow predefined criteria based on Table-1. If Hb exceeds 12 gm/dl, desidustat will be interrupted for 14 days and restarted at one dose lower when Hb falls below 11.5 gm/dl. Dose adjustment shall be done within the range of 25 mg-150 mg. Dose shall not exceed 150 mg three times a week during the study (fig 1.). These adjustments are intended to safely guide treatment toward the desired hemoglobin response while minimizing the risk of excessive erythropoiesis. If during the study period, Hb drops below 6 g/dL or 2 g/dL from baseline, necessary rescue medication (e.g., RBC transfusion or therapy approved for SCD) will be given along with continued dosing of IP, which shall be recorded in the CRF. Table 1: Dose Adjustment Criteria Change in Hb g/dL at Week 4 Hb 11 to 12 g/dL Hb >12 g/dL <1.0 increase Increase the dose Maintain the dose Maintain the dose Interrupt the treatment for 14 days, Initiate one lower dose when Hb 2.0 increase Decrease the dose Decrease the dose Decrease the dose Participant’s study treatment should be discontinued/withdrawn if: ▪ Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the opinion of the investigator/medical expert, for safety, behavioural, or compliance reasons. ▪ Any participant who requires the use of a restricted medication as per investigator discretion. ▪ Participant whose hemoglobin drops below 6 g/dL for two consecutive visits. ▪ Participant becomes pregnant ▪ Lack of compliance to the study protocol as per the investigator’s opinion ▪ Withdrawal of consent (A participant may withdraw consent from the study at any time at his/her own request Strategies to improve adherence to interventions {11c} Participants will be given a patient diary to record consumption of trial medication. Designated site staff will review patient diary and sensitize participant at each visit for treatment compliance. Relevant concomitant care permitted or prohibited during the trial {11d} Oral or intravenous iron, vitamin B12 & folic acid supplementation is permitted to maintain adequate iron status for Hb response during the trial based on investigator’s discretion. Treatment of common ailments (influenza, headache, nausea) and concurrent non-communicable disease (diabetes mellitus, hypertension) are allowed during trial and to be documented in CRF. Concomitant medications for pain management of vaso-occlusive crisis are permitted. Participants who were already on therapy for sickle cell disease (Crizanlizumab, L-glutamine, and hydroxyurea) at screening shall continue to receive the treatment at same dose throughout the study. Initiation or dose modification of treatment with these agents during the trial is not permitted. Provisions for post-trial care {30} As this is a proof-of-concept clinical trial, no post-trial care or continued access to the investigational product will be provided to participants following completion of the study. All subjects will be closely monitored throughout the study duration and if any medical issues arise related to study participation, appropriate medical care will be provided as per protocol and applicable regulatory and ethical guidelines. Outcomes {12} All the primary and secondary outcome measures will be compared between desidustat and placebo across all 3 cohorts from baseline to week 8. Primary Outcome measure is Hemoglobin (Hb) Response Rate defined as proportion of patients achieving a Hb response, defined as an increase of ≥ 1 g/dL in hemoglobin concentration. Secondary Outcomes are as follows: 1. Mean Change in Hemoglobin 2. Mean change in Biomarkers of Hemolysis: o Lactate dehydrogenase (LDH) o Total, direct, and indirect bilirubin o Absolute and percentage reticulocyte count o Serum haptoglobin o Serum potassium 3. Blood Transfusion Requirement : The proportion of patients requiring at least one blood transfusion 4. Vaso-occlusive Crisis (VOC) : The proportion of patients experiencing at least one vaso-occlusive crisis 5. Mean change in the percentage of hemoglobin S assessed by high-performance liquid chromatography (HPLC) 6. Safety Assessments : The proportion of patients experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and any clinically significant abnormalities observed during physical examination or laboratory safety parameters Participant timeline {13} The study comprises a screening period (up to 28 days), an 8-week treatment period, and a follow-up visit at Week 10. Dose adjustment is permitted at Week 4 based on hemoglobin response, with a maximum dose cap of 150 mg TID weekly (Fig 2). Sample size {14} Given the proof-of-concept nature of the study, no formal sample size calculation was done, and 24 participants (6 on Desidustat and 2 on placebo per cohort) will be enrolled. Recruitment {15} To ensure timely recruitment, sites with proven feasibility and patient availability will be selected. Proactive pre-screening, clear eligibility criteria, engagement of investigators and follow-up monitoring site visits will support efficient enrollment. Assignment of interventions: allocation Sequence generation {16a} Participants will be randomly assigned to receive either Desidustat or placebo across three parallel cohorts based on a computer-generated randomization schedule using SAS ® software (version 9.4 or higher, SAS Institute Inc., USA). Blinding will be maintained through the use of visually identical placebo tablets for both, participants and study personnel, including investigators. The first dose of the study drug is being administered under medical supervision. Concealment mechanism {16b} This study has a central integrated IWRS system for random assignment of participants across all the three arms. The service is provided by third party vendor. Implementation {16c} The independent biostatistician from the sponsor will prepare a randomization list which would be provided to third party vendor to integrate in IWRS system followed by enrolment of subjects by the site using the software to assign the random intervention from the 3 cohorts centrally. Assignment of interventions: Blinding Who will be blinded {17a} In this double-blind trial both participants and investigators along with the site staff will be unaware of treatment allocation. Blinding will be ensured by using a placebo that looks identical to investigational product. Procedure for unblinding if needed {17b} In a medical emergency, the investigator can unblind a participant’s treatment, after notifying the Sponsor. The unblinding details will be provided by sponsor designated independent statistician. Data collection and management Plans for assessment and collection of outcomes {18a} All data generated by the site personnel will be captured at each study centre using case reports forms (CRFs). Data from external sources (such as laboratory data) will be imported/entered into the database. Source documents will be filed at the Investigator’s site. Plans to promote participant retention and complete follow-up {18b} To promote participant retention, regular site monitoring visits will be scheduled along with setting up reminder systems for participants. Any barriers to follow up will be promptly identified and addressed. Data management {19} A separate data management plan will be prepared to address data entry in electronic data capture (EDC) system. An independent third-party vendor will be appointed to provide the EDC platform, and they will provide their services in maintaining data quality to sponsor. Confidentiality {27} Participant confidentiality will be ensured by assigning unique identification codes to each participant, storage of data in secured password protected system, confidential monitoring and audits visits, and anonymized published results. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable Statistical methods Statistical methods for primary and secondary outcomes {20a} Statistical analysis will be performed using SAS ® software (version 9.4 or higher). No formal hypothesis testing or. Details regarding statistical methods to be used in protocol will be captured in statistical analysis plan prior to database lock. Interim analyses {21b} No interim efficacy analyses will be performed. Methods for additional analyses (e.g. subgroup analyses) {20b} Not applicable Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Statistical analysis will be conducted on three populations: modified intent-to-treat (mITT) population, which includes all treated patients with at least one post-baseline assessment; per-protocol (PP) population, including patients who complete the study without major protocol deviations; and the safety population, comprising all patients who received at least one dose of study medication. Efficacy data will be summarized descriptively, with the last observation carried forward (LOCF) method used for missing data in the mITT analysis. Plans to give access to the full protocol, participant level-data and statistical code {31c} Not applicable Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} This project will be coordinated by Zydus lifesciences limited along with ICMR. On-site trial monitoring shall be carried out at least three times, before (pre-trial), during (periodic) and after the trial (completion/termination), by the sponsor’s Clinical Research Associate/Study Monitor. No steering committee has been formed for this study. Composition of the data monitoring committee, its role and reporting structure {21a} A Data Safety Monitoring Board will be established to monitor data and ensure safety of the participants enrolled in this study. DSMB consists of a chairperson, a medical expert in the relevant therapeutic area and one statistician. DSMB responsibilities, authorities, and procedures are documented in a separate DSMB charter. Interim safety data of first 12 participants (04 participants in each cohort) up to 14 days after randomization is going to be presented to the independent DSMB in blinded manner. The decision of continuation of the trial will depend on the opinion of the DSMB Adverse event reporting and harms {22} Investigators will review all relevant documentation for any AE/SAE and record it in participant's medical records and CRF. AEs will be treated appropriately, and all treatments (including dose adjustments, hospitalizations, etc.) will be documented. AEs will be followed until resolution, stabilization, or loss to follow-up. AEs should be documented as: · Persistent: continuous without resolution; update CRF if severity increases, or event becomes serious · Recurrent: resolves and reappears, each recurrence will be documented separately · Cascade Events : both primary and severe/serious secondary events will be recorded independently · Diagnosis vs. Symptoms : Use of single diagnosis will be done if established; otherwise all symptoms will be documented separately until diagnosis is available. Deaths: All deaths during the AE reporting period will be recorded and reported immediately. Death is considered an outcome; the underlying condition/event will be reported as a single AE. Terms like "sudden death" or "unexplained death" should be used per definitions until a cause is determined. Pre-existing Medical Conditions: These should only be recorded as AEs if worsened during the study, with descriptors indicating change (e.g., “more frequent headaches”). Assessment of Intensity/Severity will be graded as per CTCAE guidelines v5.0: · Grade 1 : Mild · Grade 2 : Moderate · Grade 3 : Severe · Grade 4 : Life-threatening · Grade 5 : Death related to AE Investigators will assess causality (WHO-UMC causality assessment scale) based on temporal relationship, alternative causes, de-challenge/re-challenge, and study drug profile. Causality categories include: · Certain · Probable/Likely · Possible · Unlikely · Conditional/Unclassified · Unassessable/Unclassifiable Assessments will be signed/dated with clinical justification and may be updated with new information. AEs are "unexpected" if not listed in the reference safety information (Investigator’s Brochure or DCGI-approved package insert) or if differing in specificity or severity. Investigators will pursue supplemental evaluations as needed and submit updated information within 24 hours of awareness of a Serious adverse event (SAE) to Central Licensing Authorities, Sponsor and Ethics Committee followed by a detailed report to regulatory authorities, ethics committee, and institution head within 14 days. Frequency and plans for auditing trial conduct {23} Quality compliance and Quality assurance audit of this trial will be conducted in timely. The quality compliance and assurance auditors will have access to all medical records, the investigator’s trial related files and correspondence, and the informed consent form documentation that is relevant to this clinical trial. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Important protocol amendments will be approved by respective Institutional ethics committee followed by notification to DCGI. Dissemination plans {31a} After trial completion and compilation of results, clinical study report will be prepared. Post that, the results will be published. Publication will comply with the obligations of ICMJE (International Committee of Medical Journal Editors) Discussion Sickle cell disease (SCD) remains a significant public health concern in India, particularly among tribal populations, with an estimated 20 million affected individuals and approximately 50,000 children born with sickle cell anemia each year. Current treatment options, such as hydroxyurea and blood transfusions, have limitations including variable efficacy, side effects, and accessibility issues. Therefore, there is an urgent need for novel, effective, and accessible therapies to manage anemia associated with SCD. Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), has been developed to stimulate endogenous erythropoietin production, thereby promoting erythropoiesis and improving iron metabolism. In Phase I trial, Desidustat was safe and well tolerated till 300 mg in healthy subjects. In Phase Ib/IIa trial, Desidustat till 150 mg was safe and well tolerated in subjects with anemia in dialysis dependent chronic kidney disease subjects. In phase II trial, three doses (100, 150 and 200 mg) of Desidustat were administered to the pre-dialysis CKD subjects. Two Phase III trials have been conducted with 100 mg initial dose in CKD subjects not dependent on dialysis and 100 mg/125mg/150mg (based on prior ESA use) in subject’s dependent on dialysis [ 10 ]. Phase III trials concluded that these doses are sufficient to raise hemoglobin to target range of (10–12 g/dL) and maintain throughout the trial without any safety concerns and based on these studies Desidustat got marketing approval in India for treating anemia in chronic kidney disease (CKD) patients (non-dialysis and dialysis dependent subjects) [ 10 ]. These findings provide a rationale for exploring its potential benefits in SCD patients. In this study, dose of 50 mg, 100 mg and 150 mg Desidustat tablets have been selected to optimize therapeutic dose for sickle cell disease subjects. Proposed mechanism of action of desidustat in SCD [ 11 ]: a. Increased EPO production leading to increase in RBC/Hb level b. Increasing production of y-globin from liver leading to increased synthesis of Hb F and inhibiting sickling (increase RBC survival) and preventing VOC episodes. c. Improving Pyruvate kinase activity, improving RBC energy metabolism leading to decreased hemolysis and may also contribute to reduced oxidative stress. The current Phase IIa, double-blind, randomized, placebo-controlled, multicenter, proof-of-concept study aims to evaluate the efficacy and safety of Desidustat in adult Indian patients with SCD. The study design includes three dosing cohorts (50 mg, 100 mg, and 150 mg) to assess the dose-response relationship and identify the optimal therapeutic dose. Participants will receive Desidustat or placebo orally three times a week for eight weeks, with the primary endpoint being the proportion of patients achieving a hemoglobin response, defined as an increase of ≥ 1 g/dL from baseline to Week 8 compared to placebo. Secondary endpoints include mean changes in hemoglobin level, biomarkers related to hemolysis (such as LDH, bilirubin, reticulocyte count, serum haptoglobin, and serum potassium), the proportion of patients requiring blood transfusions, the incidence of vaso-occlusive crises, and changes in the percentage of HbS. Safety assessments will involve monitoring treatment-emergent adverse events, clinical laboratory parameters, ECGs, vital signs, and physical examination. An independent Data Safety Monitoring Board (DSMB) will oversee the study, reviewing interim safety data from the first 12 participants (four in each cohort) up to 14 days after randomization. This approach ensures participant safety and aligns with best practices in clinical research. Potential risks of a participant’s study involvement include unknown AEs, general risks associated with frequent clinic visits, laboratory blood draws, and the associated pain and discomfort of phlebotomy. Strategies to mitigate these risks include close monitoring of lab values as well as AEs.The outcomes of this study could pave the way for larger, more definitive trials and potentially offer a new therapeutic option for managing anemia in SCD, contributing to the goals of the National Sickle Cell Anaemia Elimination Mission. The collaboration between Zydus Lifesciences and the Indian Council of Medical Research (ICMR) exemplifies a strategic public-private partnership aimed at addressing the unmet medical needs of SCD patients in India. DESI.23.001 is currently on going with active recruitment at 4 sites across India. The expected completion of study by all participants is by August-2025. Study results (Clinical Study Report) are expected to get finalized by December- 2025. Trial status The study protocol (Version 1, dated July 12, 2023) has reached a significant milestone. Recruitment commenced on July 30, 2024, and was completed ahead of schedule on May 22, 2025, across all sites. Although recruitment was initially expected to conclude in June-July 2025, the competitive nature of the study led to earlier completion. Follow-up activities are ongoing and expected to continue until the end of July 2025. Abbreviations SCD Sickle cell disease HIF-PHI Hypoxia-inducible factor prolyl hydroxylase inhibitor RBC Red Blood Cells CDSCO Central Drugs Standard Control Organization ICMR Indian Council of Medical Research VOCs Vaso-occlusive crises HU Hydroxyurea HbF Fetal hemoglobin EPO Erythropoietin CKD chronic kidney disease DSMB Data Safety Monitoring Board AE Adverse event LDH Lactate dehydrogenase HPLC High-performance liquid chromatography TEAEs Treatment-emergent adverse events SAEs Serious adverse events CRF Case reports forms LOCF Last observation carried forward ICMJE International Committee of Medical Journal Editors Declarations Acknowledgements We would like to acknowledge the Clinical Studies and Trials Unit team of ICMR, New Delhi involved site initiation visits and onsite monitoring. Also, we would like to acknowledge all the Zydus scientific team and all researchers involved in this trial for their dedication to recruiting and caring for the participants. Authors’ contributions {31b} DP and KK are the principal investigator who devised the trial concept and designed the trial, with inputs from SS. MG, GK, SR, SK, and AM responsible for trial initiation, trial management, and monitoring activities and also wrote the first draft of the manuscript. All authors contributed to subsequent drafts and approved the final version. All authors adhere to the authorship guidelines and have agreed to publication. Funding {4} This clinical trial is being co-funded by the Indian Council of Medical Research (ICMR, New Delhi) under the Development Division under INTENT/NHRP for the 2024-25 with Project ID NHRP06044 and Zydus Lifescience Limited, Gujrat, India. Availability of data and materials {29} The datasets generated and/or analyzed during the current study are not publicly available due to them containing private health information (PHI) but will be available on reasonable request. Ethics approval and consent to participate {24} The trial complies with approved protocol, ICH-GCP guidelines, Indian GCP, New Drugs and Clinical Trial Rules, 2019, and all applicable regulatory requirements. The study commenced after receiving approval from a CDSCO-registered Ethics Committee (EC) for protocol, informed consent form (ICF), and participant information sheet. The study is approved from CDSCO, CT NOC No. is CT/SND/27/2023, protocol number DESI.23.001, registered on 12 June 2023. All participants will provide written informed consent before any trial-related procedures. For illiterate participants, the consent process will involve a verbal explanation in a language understood by the participant, a thumb impression, and the signature of an impartial witness. Participants will receive a copy of the signed consent form. Medical records may be accessed by authorized sponsor representatives, EC members, and regulatory inspectors for monitoring and audit purposes. Amendments to the consent documents will require EC approval and re-consent of affected participants, as applicable. Consent for publication {32} This is the study protocol manuscript and no patient data is submitted as a part of this document. Consent for publication of results is being obtained at the time of obtaining informed consent during enrollment process. The patient information material and informed consent form will be available from ICMR and Zydus Lifesciences Limited upon reasonable request. Competing interests {28} The following individuals are employed by and have affiliations with the organizations listed: - MG, GK, SR, SK, and AM: Indian Council of Medical Research (ICMR), co-funder of the study. DP, KK, and SS: Zydus Lifescience Limited, co-funder of the study. References Mehanna AS. Sickle cell anemia and antisickling agents then and now. Cur Med Chem. 2001;8(2):79–88. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of sickle cell disease. Annu Rev Pathol Mech Dis. 2019;14:263–92. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358(13):1362–9. Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 2010;115(26):5300–11. Matte A, Zorzi F, Mazzi F, Federti E, Olivieri O, De Franceschi L. New therapeutic options for the treatment of sickle cell disease. Mediterr J Hematol Infect Dis 2019; 11(1). Dhillon S, Desidustat. First Approval Drugs. 2022;82(11):1207–12. Janssens LK, Stove CP. Sensing an oxygen sensor: development and application of activity-based assays directly monitoring HIF heterodimerization. Anal Chem. 2021;93:14462–70. Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, et al. Phase I clinical study of ZYAN1, a novel prolyl-hydroxylase (PHD) inhibitor to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers. Clin Pharmacokinet. 2018;57:87–102. Parmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Investigators T et al. 2019. Outcomes of desidustat treatment in people with anemia and chronic kidney disease: a phase 2 study. Am J Nephrol. 2019;49(6);470–478. Gang S, Khetan P, Varade D, Chinta VR, Mavani S, Gupta U, et al. Study Investigator Group. Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D). Am J Nephrol. 2022;53(5):343–51. Joharapurkar A, Pandya V, Patel H, Jain M, Desai R. Desidustat: a novel PHD inhibitor for the treatment of CKD-induced anemia. Front Nephrol. 2024;22:4:1459425. Supplementary Files Appendix.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 02 Oct, 2025 Reviewers invited by journal 02 Oct, 2025 Editor assigned by journal 15 Jul, 2025 First submitted to journal 14 Jul, 2025 Editorial decision: Major revision 07 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6911159","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":523847260,"identity":"77030bd8-84c3-4e37-8033-42c96d872978","order_by":0,"name":"Mayank Gangwar","email":"","orcid":"","institution":"ICMR: Indian Council of Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Mayank","middleName":"","lastName":"Gangwar","suffix":""},{"id":523847261,"identity":"61f06240-9000-4bc3-84cd-67223bd68f4f","order_by":1,"name":"Gunjan Kumar","email":"","orcid":"","institution":"ICMR: Indian Council of Medical 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1","display":"","copyAsset":false,"role":"figure","size":16863,"visible":true,"origin":"","legend":"\u003cp\u003eDose adjustment regimen\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6911159/v1/2c644895f500b32686ab98d3.png"},{"id":93638716,"identity":"7eab0e57-2bd1-4bba-abc9-e0465ada6309","added_by":"auto","created_at":"2025-10-16 01:59:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":193653,"visible":true,"origin":"","legend":"\u003cp\u003eDetailed study workflow for clinical trial procedure\u003c/p\u003e","description":"","filename":"floatimage213.png","url":"https://assets-eu.researchsquare.com/files/rs-6911159/v1/87f4ceb55910ca43f1c8185d.png"},{"id":93638717,"identity":"07e569a6-e21f-4b41-ac0f-74c5bfdb287d","added_by":"auto","created_at":"2025-10-16 01:59:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":235021,"visible":true,"origin":"","legend":"\u003cp\u003eProposed mechanism of action of desidustat in SCD\u003c/p\u003e","description":"","filename":"floatimage314.png","url":"https://assets-eu.researchsquare.com/files/rs-6911159/v1/b7b22c8ff6bd7b96ed44a155.png"},{"id":93640201,"identity":"bb91fe90-9316-486b-beaa-672e70981e96","added_by":"auto","created_at":"2025-10-16 02:23:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2091569,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6911159/v1/f6551564-3128-4d17-a99e-4cd581856e73.pdf"},{"id":93638720,"identity":"70a0f0e6-48c7-4320-97e1-e62516b417e3","added_by":"auto","created_at":"2025-10-16 01:59:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23668,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-6911159/v1/4107a48892656e3ecc1f9f9f.docx"}],"financialInterests":"","formattedTitle":"Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Desidustat Oral Tablet in Sickle Cell Disease: A Phase IIa Proof-of-Concept Evaluation","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSickle cell disease (SCD) is a hereditary hemoglobinopathy caused by a single point mutation (GAG to GTG) in the \u0026beta;-globin gene, resulting in the substitution of glutamic acid with valine at position six (\u0026beta;Glu6Val) [1]. This mutation leads to the production of hemoglobin S (HbS), which polymerizes under deoxygenated conditions, distorting red blood cells (RBCs) into a sickled shape. These sickled RBCs are rigid and adhesive, leading to microvascular occlusion, recurrent vaso-occlusive crises (VOCs), chronic hemolytic anemia, and progressive multi-organ damage. The lifespan of sickled RBCs is significantly reduced (approximately 16 days) compared to normal RBCs (approximately 120 days), contributing to the chronic anemia observed in SCD patients. The pathophysiology of SCD involves a complex interplay of four interrelated processes: HbS polymerization, impaired blood flow and vaso-occlusion, hemolysis-mediated endothelial dysfunction, and sterile inflammation triggered by innate immune pathways. These mechanisms collectively result in acute and chronic complications such as pain crises, stroke, acute chest syndrome, and organ failure [2]. Current treatment strategies primarily focus on symptom management and reduction of disease severity, but curative approaches such as hematopoietic stem cell transplantation are limited by donor availability and associated risks.\u003c/p\u003e\n\u003cp\u003eHydroxyurea (HU), the first FDA-approved disease-modifying therapy for SCD, exerts its benefits primarily by inducing fetal hemoglobin (HbF) production, which inhibits HbS polymerization. However, HU has limitations including variable efficacy, poor adherence, and myelosuppressive side effects [3, 4]. In 2019, crizanlizumab, an anti-P-selectin monoclonal antibody, was approved by USFDA to reduce the frequency of vaso-occlusive crises (VOCs) [5]. However, SCD remains a disease with considerable unmet clinical need.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDesidustat, a novel hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) inhibitor, offers a promising approach for SCD by pharmacologically stimulating erythropoiesis through activation of the HIF pathway. This mechanism mimics the physiological response to hypoxia, increasing endogenous erythropoietin (EPO) production and supporting red blood cell production. Desidustat has demonstrated efficacy and safety in Phase I\u0026ndash;III trials for treating anemia in chronic kidney disease (CKD) patients, both on dialysis and not on dialysis and has got marketing approval in India in March-2022 [6].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIn vitro\u003c/em\u003e studies have shown that Desidustat can reduce sodium metabisulfite-induced sickling in RBCs from SCD patients, suggesting potential disease-modifying activity. Preclinical studies further support its safety, bioavailability, and hematopoietic efficacy across various animal models. Desidustat exhibited minimal genotoxicity and no significant adverse effects on reproductive parameters in animal studies [7].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinically, Desidustat was well tolerated up to 300 mg in Phase I trials [8] and showed a dose-dependent increase in hemoglobin levels in CKD patients during subsequent Phase II and III studies, with no serious adverse events or persistent lab abnormalities reported [9]. Given this encouraging evidence, a Phase IIa proof-of-concept clinical trial has been designed to evaluate the safety and efficacy of Desidustat in adults with SCD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial involves administration of Desidustat oral tablets (50, 100, or 150 mg) three times per week over an eight-week period to assess changes in hemoglobin level while monitoring adverse effects. This trial aims to prove the potential of desidustat as a novel, orally administered therapy that could address the limitations of current treatments, such as hydroxyurea and blood transfusions with a mechanism that complements and potentially surpasses existing therapies. \u0026nbsp;Desidustat has the potential to be an integral part of SCD management, improving patient outcomes, quality of life and cost-effectiveness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe purpose of this study is to evaluate the efficacy and safety of Desidustat oral tablet three times per week for 08 weeks in sickle cell disease patients comapred to placebo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a multicenter, Phase IIa, randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept clinical trial evaluating the efficacy and safety of Desidustat in adult Indian patients with SCD. A total of 24 participants will be enrolled and randomized into three dose cohorts (50 mg, 100 mg, and 150 mg), each including 6 participants receiving Desidustat and 2 receiving placebo, administered orally three times a week for 8 weeks. Interim blinded safety data from the first 12 participants will be reviewed by an independent Data Safety Monitoring Board (DSMB). Efficacy will be assessed by change in hemoglobin levels and other hematologic parameters. Safety evaluations include adverse event monitoring, physical examination, vital signs, ECG, echocardiography, and laboratory assessments.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study will be conducted across 5 centers in India (2 private multispecialty hospitals and 2 academic hospitals, 1 government hospital). The list of trial sites can be found on Clinical Trial Registry- India website.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion criteria:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Adults aged \u0026ge;18 years.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Indian male or female with confirmed sickle cell disease (any genotype) by laboratory evidence (e.g., hemoglobin electrophoresis, HPLC, or genetic testing).\u003c/p\u003e\n\u003cp\u003e\u0026middot; Hemoglobin: 7\u0026ndash;11 g/dL for males; 6.5\u0026ndash;11 g/dL for females.\u003c/p\u003e\n\u003cp\u003e\u0026middot; At least 1 episode of documented vaso-occlusive crisis (VOC) in the past 12 months.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Serum ferritin \u0026ge;100 ng/mL and/or transferrin saturation (TSAT) \u0026ge;20% at screening.\u003c/p\u003e\n\u003cp\u003e\u0026middot; No significant vitamin B12 or folate deficiency.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Stable dose of hydroxyurea, L-glutamine, or crizanlizumab (if applicable) for \u0026ge;60 days before consent.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Agreement to use adequate contraception during the study and for 30 days after the last dose.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Signed informed consent (or thumb impression with impartial witness for illiterate participants).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Recent blood transfusion (\u0026lt;30 days), hospitalization for VOC (\u0026lt;14 days), or participation in another clinical trial (\u0026lt;3 months).\u003c/p\u003e\n\u003cp\u003e\u0026middot; Current treatment with Voxelotor, erythropoietin, or hematopoietic growth factors.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Significant lab abnormalities (e.g., low neutrophils \u0026le; 1.5 x 10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L or platelets \u0026le; 100 x 10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L, high bilirubin \u0026gt;3.5 mg/dL or ALT \u0026ge; 2.5 times ULN).\u003c/p\u003e\n\u003cp\u003e\u0026middot; For diabetic patients, HbA1c \u0026gt; 9 g/dL.\u003c/p\u003e\n\u003cp\u003e\u0026middot; History of chronic inflammatory disease, systemic disorders or diseases, stroke or intracranial hemorrhage, cirrhosis, severe renal dysfunction or on chronic dialysis, thrombosis, or pancreatitis/MI within 6 months.\u003c/p\u003e\n\u003cp\u003e\u0026middot; History of severe allergic or hypersensitivity reaction to investigational products and its excipients.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Presence or a history of bleeding disorders or clinical conditions\u003c/p\u003e\n\u003cp\u003e\u0026middot; Active infections (e.g., HIV, Hepatitis A/B/C, malaria), or recent IV antibiotic or iron treatment (within 14 days prior to enrolment).\u003c/p\u003e\n\u003cp\u003e\u0026middot; Medical conditions compromising safety (e.g., cardiovascular disease, bleeding disorders, malignancy, uncontrolled diabetes, inflammatory diseases).\u003c/p\u003e\n\u003cp\u003e\u0026middot; Any major surgery within 90 days prior to randomization, and minor surgery within 30 days prior to randomization\u003c/p\u003e\n\u003cp\u003e\u0026middot; Pregnancy, lactation, or inadequate birth control in women of childbearing potential.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Substance abuse, smoking/tobacco \u0026gt;10/day, or difficulty donating blood.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Clinically significant ECG, echocardiogram, or systemic disorders.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Need for anticoagulation therapy that may pose safety risks.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u0026nbsp; \u0026nbsp;Investigator-determined conditions that may affect safety or data integrity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten Informed consent will be taken by Principal investigator/designee in this trial. For illiterate participants, the consent process will involve a verbal explanation in a language understood by the participant, a thumb impression, and the signature of an impartial witness. Participants will receive a copy of the signed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimen in ancillary studies, if applicable? {26b}\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dose regimen of 50, 100 mg and 150 mg Desidustat tablets three times a week for oral administration along with matching placebo have been selected to assess the therapeutic effect, safety of the drug and dose optimization for future clinical development. The doses have been selected based on previous clinical trials conducted. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants in the study will be randomly assigned to receive either Desidustat or placebo in one of three treatment cohorts (Figure 1). The study drug will be administered three times per week for a duration of eight weeks, with at least 48 hours between doses. Participants in the treatment arm will receive 50 mg, 100 mg, or 150 mg doses of Desidustat, with 150 mg dose provided as a combination of available strengths (50 mg, 100 mg). The placebo group will follow the same schedule using matching placebo. Study drugs are packaged, labelled, and supplied by the sponsor in accordance with regulatory requirements. The investigator is responsible for confirming receipt and maintaining accurate records of IP inventory, dispensing, and return. Investigational products are being stored securely at the site and returned to the sponsor or destroyed as per protocol following drug accountability procedures. All study medications are being stored at temperatures below 30\u0026deg;C, and appropriate temperature logs are being maintained. \u0026nbsp;Participants will be advised not to consume any food 1 hour before and 2 hours after the administration of study drug.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDose modifications will be performed at week 4 based on changes in hemoglobin (Hb) levels compared to baseline. The target is to maintain Hb levels below 12 g/dL. Hb is being measured using a calibrated HemoCue device at week-4, taking the average of two readings, from EDTA or fresh blood samples. Dose adjustments will follow predefined criteria based on Table-1. If Hb exceeds 12 gm/dl, desidustat will be interrupted for 14 days and restarted at one dose lower when Hb falls below 11.5 gm/dl. \u0026nbsp; Dose adjustment shall be done within the range of 25 mg-150 mg. Dose shall not exceed 150 mg three times a week during the study (fig 1.). \u0026nbsp;These adjustments are intended to safely guide treatment toward the desired hemoglobin response while minimizing the risk of excessive erythropoiesis.\u003c/p\u003e\n\u003cp\u003eIf during the study period, Hb drops below 6 g/dL or 2 g/dL from baseline, necessary rescue medication (e.g., RBC transfusion or therapy approved for SCD) will be given along with continued dosing of IP, which shall be recorded in the CRF.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1: Dose Adjustment Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChange in Hb\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eg/dL\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;at Week 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHb \u0026lt;10\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eg/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHb 10 to 11\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eg/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHb \u0026gt;11 to 12 g/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHb \u0026gt;12\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eg/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026lt;1.0 increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eIncrease the dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eMaintain the dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eMaintain the dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 104px;\"\u003e\n \u003cp\u003eInterrupt the treatment for 14 days, Initiate one lower dose when Hb \u0026lt; 11.5 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026sup3;1.0 to \u0026le; 2.0 increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eMaintain the dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eMaintain the dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eDecrease the dose\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026gt;2.0 increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eDecrease the dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eDecrease the dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eDecrease the dose\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipant\u0026rsquo;s study treatment should be discontinued/withdrawn if:\u003c/p\u003e\n\u003cp\u003e▪ Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the opinion of the investigator/medical expert, for safety, behavioural, or compliance reasons.\u003c/p\u003e\n\u003cp\u003e▪ Any participant who requires the use of a restricted medication as per investigator discretion.\u003c/p\u003e\n\u003cp\u003e▪ Participant whose hemoglobin drops below 6 g/dL for two consecutive visits.\u003c/p\u003e\n\u003cp\u003e▪ Participant becomes pregnant\u003c/p\u003e\n\u003cp\u003e▪ Lack of compliance to the study protocol as per the investigator\u0026rsquo;s opinion\u003c/p\u003e\n\u003cp\u003e▪ Withdrawal of consent (A participant may withdraw consent from the study at any time at his/her own request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be given a patient diary to record consumption of trial medication. Designated site staff will review patient diary and sensitize participant at each visit for treatment compliance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOral or intravenous iron, vitamin B12 \u0026amp; folic acid supplementation is permitted to maintain adequate iron status for Hb response during the trial based on investigator\u0026rsquo;s discretion. Treatment of common ailments (influenza, headache, nausea) and concurrent non-communicable disease (diabetes mellitus, hypertension) are allowed during trial and to be documented in CRF. Concomitant medications for pain management of vaso-occlusive crisis are permitted. Participants who were already on therapy for sickle cell disease (Crizanlizumab, L-glutamine, and hydroxyurea) at screening shall continue to receive the treatment at same dose throughout the study. Initiation or dose modification of treatment with these agents during the trial is not permitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs this is a proof-of-concept clinical trial, no post-trial care or continued access to the investigational product will be provided to participants following completion of the study. All subjects will be closely monitored throughout the study duration and if any medical issues arise related to study participation, appropriate medical care will be provided as per protocol and applicable regulatory and ethical guidelines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the primary and secondary outcome measures will be compared between desidustat and placebo across all 3 cohorts from baseline to week 8.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Outcome measure is Hemoglobin (Hb) Response Rate\u003c/strong\u003e defined as proportion of patients achieving a Hb response, defined as an increase of \u0026ge; 1 g/dL in hemoglobin concentration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Outcomes are as follows:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. \u003cstrong\u003eMean Change in Hemoglobin\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. \u003cstrong\u003eMean change in Biomarkers of Hemolysis:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eo Lactate dehydrogenase (LDH)\u003c/p\u003e\n\u003cp\u003eo Total, direct, and indirect bilirubin\u003c/p\u003e\n\u003cp\u003eo Absolute and percentage reticulocyte count\u003c/p\u003e\n\u003cp\u003eo Serum haptoglobin\u003c/p\u003e\n\u003cp\u003eo Serum potassium\u003c/p\u003e\n\u003cp\u003e3. \u003cstrong\u003eBlood Transfusion Requirement\u003c/strong\u003e: The proportion of patients requiring at least one blood transfusion\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. \u003cstrong\u003eVaso-occlusive Crisis (VOC)\u003c/strong\u003e: The proportion of patients experiencing at least one vaso-occlusive crisis \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5. \u003cstrong\u003eMean change in the percentage of hemoglobin S\u003c/strong\u003e assessed by high-performance liquid chromatography (HPLC)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e6. \u003cstrong\u003eSafety Assessments\u003c/strong\u003e: The proportion of patients experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and any clinically significant abnormalities observed during physical examination or laboratory safety parameters\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study comprises a screening period (up to 28 days), an 8-week treatment period, and a follow-up visit at Week 10. Dose adjustment is permitted at Week 4 based on hemoglobin response, with a maximum dose cap of 150 mg TID weekly (Fig 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven the proof-of-concept nature of the study, no formal sample size calculation was done, and 24 participants (6 on Desidustat and 2 on placebo per cohort) will be enrolled.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure timely recruitment, sites with proven feasibility and patient availability will be selected. Proactive pre-screening, clear eligibility criteria, engagement of investigators and follow-up monitoring site visits will support efficient enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be randomly assigned to receive either Desidustat or placebo across three parallel cohorts based on a computer-generated randomization schedule using SAS\u003csup\u003e\u0026reg;\u003c/sup\u003e software (version 9.4 or higher, SAS Institute Inc., USA). Blinding will be maintained through the use of visually identical placebo tablets for both, participants and study personnel, including investigators. \u0026nbsp; The first dose of the study drug is being administered under medical supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has a central integrated IWRS system for random assignment of participants across all the three arms. The service is provided by third party vendor.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe independent biostatistician from the sponsor will prepare a randomization list which would be provided to third party vendor to integrate in IWRS system followed by enrolment of subjects by the site using the software to assign the random intervention from the 3 cohorts centrally.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this double-blind trial both participants and investigators along with the site staff will be unaware of treatment allocation. Blinding will be ensured by using a placebo that looks identical to investigational product.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn a medical emergency, the investigator can unblind a participant\u0026rsquo;s treatment, after notifying the Sponsor. The unblinding details will be provided by sponsor designated independent statistician.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated by the site personnel will be captured at each study centre using case reports\u003c/p\u003e\n\u003cp\u003eforms (CRFs). Data from external sources (such as laboratory data) will be imported/entered into\u003c/p\u003e\n\u003cp\u003ethe database. Source documents will be filed at the Investigator\u0026rsquo;s site.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo promote participant retention, regular site monitoring visits will be scheduled along with setting up reminder systems for participants. Any barriers to follow up will be promptly identified and addressed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA separate data management plan will be prepared to address data entry in electronic data capture (EDC) system. An independent third-party vendor will be appointed to provide the EDC platform, and they will provide their services in maintaining data quality to sponsor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipant confidentiality will be ensured by assigning unique identification codes to each participant, storage of data in secured password protected system, confidential monitoring and audits visits, and anonymized published results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis will be performed using SAS\u003csup\u003e\u0026reg;\u003c/sup\u003e software (version 9.4 or higher). No formal hypothesis testing or. Details regarding statistical methods to be used in protocol will be captured in statistical analysis plan prior to database lock.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u0026nbsp;\u003c/strong\u003eNo interim efficacy analyses will be performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis will be conducted on three populations: \u0026nbsp;modified intent-to-treat (mITT) population, which includes all treated patients with at least one post-baseline assessment; per-protocol (PP) population, including patients who complete the study without major protocol deviations; and the safety population, comprising all patients who received at least one dose of study medication. Efficacy data will be summarized descriptively, with the last observation carried forward (LOCF) method used for missing data in the mITT analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project will be coordinated by Zydus lifesciences limited along with ICMR. On-site trial monitoring shall be carried out at least three times, before (pre-trial), during (periodic) and after the trial (completion/termination), by the sponsor\u0026rsquo;s Clinical Research Associate/Study Monitor. No steering committee has been formed for this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA Data Safety Monitoring Board will be established to monitor data and ensure safety of the participants enrolled in this study. \u0026nbsp;DSMB consists of a chairperson, a medical expert in the relevant therapeutic area and one statistician. DSMB responsibilities, authorities, and procedures are documented in a separate DSMB charter. Interim safety data of first 12 participants (04 participants in each cohort) up to 14 days after randomization is going to be presented to the independent DSMB in blinded manner. The decision of continuation of the trial will depend on the opinion of the DSMB\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInvestigators will review all relevant documentation for any AE/SAE and record it in participant\u0026apos;s medical records and CRF. AEs will be treated appropriately, and all treatments (including dose adjustments, hospitalizations, etc.) will be documented. AEs will be followed until resolution, stabilization, or loss to follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAEs should be documented as:\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003ePersistent:\u003c/strong\u003e continuous without resolution; update CRF if severity increases, or event becomes serious\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eRecurrent:\u003c/strong\u003e resolves and reappears, each recurrence will be documented separately\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eCascade Events\u003c/strong\u003e: both primary and severe/serious secondary events will be recorded independently\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eDiagnosis vs. Symptoms\u003c/strong\u003e: Use of single diagnosis will be done if established; otherwise all symptoms will be documented separately until diagnosis is available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeaths:\u0026nbsp;\u003c/strong\u003eAll deaths during the AE reporting period will be recorded and reported immediately. Death is considered an outcome; the underlying condition/event will be reported as a single AE. Terms like \u0026quot;sudden death\u0026quot; or \u0026quot;unexplained death\u0026quot; should be used per definitions until a cause is determined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePre-existing Medical Conditions:\u0026nbsp;\u003c/strong\u003eThese should only be recorded as AEs if worsened during the study, with descriptors indicating change (e.g., \u0026ldquo;more frequent headaches\u0026rdquo;).\u003c/p\u003e\n\u003cp\u003eAssessment of Intensity/Severity will be graded as per CTCAE guidelines v5.0:\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eGrade 1\u003c/strong\u003e: Mild\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eGrade 2\u003c/strong\u003e: Moderate\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eGrade 3\u003c/strong\u003e: Severe\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eGrade 4\u003c/strong\u003e: Life-threatening\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eGrade 5\u003c/strong\u003e: Death related to AE\u003c/p\u003e\n\u003cp\u003eInvestigators will assess causality (WHO-UMC causality assessment scale) based on temporal relationship, alternative causes, de-challenge/re-challenge, and study drug profile. Causality categories include:\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eCertain\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eProbable/Likely\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003ePossible\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eUnlikely\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eConditional/Unclassified\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eUnassessable/Unclassifiable\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAssessments will be signed/dated with clinical justification and may be updated with new information. AEs are \u0026quot;unexpected\u0026quot; if not listed in the reference safety information (Investigator\u0026rsquo;s Brochure or DCGI-approved package insert) or if differing in specificity or severity.\u003c/p\u003e\n\u003cp\u003eInvestigators will pursue supplemental evaluations as needed and submit updated information within 24 hours of awareness of a Serious adverse event (SAE) to\u0026nbsp;Central Licensing Authorities, Sponsor and Ethics Committee\u0026nbsp;followed by a detailed report to regulatory authorities, ethics committee, and institution head within 14 days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQuality compliance and Quality assurance audit of this trial will be conducted in timely. The quality compliance and assurance auditors will have access to all medical records, the investigator\u0026rsquo;s trial related files and correspondence, and the informed consent form documentation that is relevant to this clinical trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eImportant protocol amendments will be approved by respective Institutional ethics committee followed by notification to DCGI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter trial completion and compilation of results, clinical study report will be prepared. Post that, the results will be published. Publication will comply with the obligations of ICMJE (International Committee of Medical Journal Editors)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSickle cell disease (SCD) remains a significant public health concern in India, particularly among tribal populations, with an estimated 20\u0026nbsp;million affected individuals and approximately 50,000 children born with sickle cell anemia each year. Current treatment options, such as hydroxyurea and blood transfusions, have limitations including variable efficacy, side effects, and accessibility issues. Therefore, there is an urgent need for novel, effective, and accessible therapies to manage anemia associated with SCD.\u003c/p\u003e\u003cp\u003eDesidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), has been developed to stimulate endogenous erythropoietin production, thereby promoting erythropoiesis and improving iron metabolism. In Phase I trial, Desidustat was safe and well tolerated till 300 mg in healthy subjects. In Phase Ib/IIa trial, Desidustat till 150 mg was safe and well tolerated in subjects with anemia in dialysis dependent chronic kidney disease subjects. In phase II trial, three doses (100, 150 and 200 mg) of Desidustat were administered to the pre-dialysis CKD subjects. Two Phase III trials have been conducted with 100 mg initial dose in CKD subjects not dependent on dialysis and 100 mg/125mg/150mg (based on prior ESA use) in subject\u0026rsquo;s dependent on dialysis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePhase III trials concluded that these doses are sufficient to raise hemoglobin to target range of (10\u0026ndash;12 g/dL) and maintain throughout the trial without any safety concerns and based on these studies Desidustat got marketing approval in India for treating anemia in chronic kidney disease (CKD) patients (non-dialysis and dialysis dependent subjects) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These findings provide a rationale for exploring its potential benefits in SCD patients. In this study, dose of 50 mg, 100 mg and 150 mg Desidustat tablets have been selected to optimize therapeutic dose for sickle cell disease subjects.\u003c/p\u003e\u003cp\u003eProposed mechanism of action of desidustat in SCD [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]:\u003c/p\u003e\u003cp\u003ea. Increased EPO production leading to increase in RBC/Hb level\u003c/p\u003e\u003cp\u003eb. Increasing production of y-globin from liver leading to increased synthesis of Hb F and inhibiting sickling (increase RBC survival) and preventing VOC episodes.\u003c/p\u003e\u003cp\u003ec. Improving Pyruvate kinase activity, improving RBC energy metabolism leading to decreased hemolysis and may also contribute to reduced oxidative stress.\u003c/p\u003e\u003cp\u003eThe current Phase IIa, double-blind, randomized, placebo-controlled, multicenter, proof-of-concept study aims to evaluate the efficacy and safety of Desidustat in adult Indian patients with SCD. The study design includes three dosing cohorts (50 mg, 100 mg, and 150 mg) to assess the dose-response relationship and identify the optimal therapeutic dose. Participants will receive Desidustat or placebo orally three times a week for eight weeks, with the primary endpoint being the proportion of patients achieving a hemoglobin response, defined as an increase of \u0026ge;\u0026thinsp;1 g/dL from baseline to Week 8 compared to placebo. Secondary endpoints include mean changes in hemoglobin level, biomarkers related to hemolysis (such as LDH, bilirubin, reticulocyte count, serum haptoglobin, and serum potassium), the proportion of patients requiring blood transfusions, the incidence of vaso-occlusive crises, and changes in the percentage of HbS. Safety assessments will involve monitoring treatment-emergent adverse events, clinical laboratory parameters, ECGs, vital signs, and physical examination. An independent Data Safety Monitoring Board (DSMB) will oversee the study, reviewing interim safety data from the first 12 participants (four in each cohort) up to 14 days after randomization. This approach ensures participant safety and aligns with best practices in clinical research.\u003c/p\u003e\u003cp\u003ePotential risks of a participant\u0026rsquo;s study involvement include unknown AEs, general risks associated with frequent clinic visits, laboratory blood draws, and the associated pain and discomfort of phlebotomy. Strategies to mitigate these risks include close monitoring of lab values as well as AEs.The outcomes of this study could pave the way for larger, more definitive trials and potentially offer a new therapeutic option for managing anemia in SCD, contributing to the goals of the National Sickle Cell Anaemia Elimination Mission. The collaboration between Zydus Lifesciences and the Indian Council of Medical Research (ICMR) exemplifies a strategic public-private partnership aimed at addressing the unmet medical needs of SCD patients in India.\u003c/p\u003e\u003cp\u003eDESI.23.001 is currently on going with active recruitment at 4 sites across India. The expected completion of study by all participants is by August-2025. Study results (Clinical Study Report) are expected to get finalized by December- 2025.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTrial status\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe study protocol (Version 1, dated July 12, 2023) has reached a significant milestone. Recruitment commenced on July 30, 2024, and was completed ahead of schedule on May 22, 2025, across all sites. Although recruitment was initially expected to conclude in June-July 2025, the competitive nature of the study led to earlier completion. Follow-up activities are ongoing and expected to continue until the end of July 2025.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSCD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eSickle cell disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHIF-PHI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHypoxia-inducible factor prolyl hydroxylase inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eRBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eRed Blood Cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eCDSCO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eCentral Drugs Standard Control Organization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eICMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eIndian Council of Medical Research\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eVOCs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eVaso-occlusive crises\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHydroxyurea\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHbF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eFetal hemoglobin\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eEPO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eErythropoietin\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eCKD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003echronic kidney disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eDSMB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eData Safety Monitoring Board\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eAdverse event\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eLDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eLactate dehydrogenase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHPLC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHigh-performance liquid chromatography\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eTEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eTreatment-emergent adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eSerious adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eCRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eCase reports forms\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eLOCF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eLast observation carried forward\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eICMJE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eInternational Committee of Medical Journal Editors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the Clinical Studies and Trials Unit team of ICMR, New Delhi involved site initiation visits and onsite monitoring. Also, we would like to acknowledge all the Zydus scientific team and all researchers involved in this trial for their dedication to recruiting and caring for the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDP and KK are the principal investigator who devised the trial concept and designed the trial, with inputs from SS. MG, GK, SR, SK, and AM responsible for trial initiation, trial management, and monitoring activities and also wrote the first draft of the manuscript. All authors contributed to subsequent drafts and approved the final version. All authors adhere to the authorship guidelines and have agreed to publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis clinical trial is being co-funded by the Indian Council of Medical Research (ICMR, New Delhi) under the Development Division under INTENT/NHRP for the 2024-25 with Project ID NHRP06044 and Zydus Lifescience Limited, Gujrat, India.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to them containing private health information (PHI) but will be available on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial complies with approved protocol, ICH-GCP guidelines, Indian GCP, New Drugs and Clinical Trial Rules, 2019, and all applicable regulatory requirements. The study commenced after receiving approval from a CDSCO-registered Ethics Committee (EC) for protocol, informed consent form (ICF), and participant information sheet. The study is approved from CDSCO, CT NOC No. is CT/SND/27/2023, protocol number DESI.23.001, registered on 12 June 2023. All participants will provide written informed consent before any trial-related procedures. For illiterate participants, the consent process will involve a verbal explanation in a language understood by the participant, a thumb impression, and the signature of an impartial witness. Participants will receive a copy of the signed consent form. Medical records may be accessed by authorized sponsor representatives, EC members, and regulatory inspectors for monitoring and audit purposes. Amendments to the consent documents will require EC approval and re-consent of affected participants, as applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is the study protocol manuscript and no patient data is submitted as a part of this document. Consent for publication of results is being obtained at the time of obtaining informed consent during enrollment process. The patient information material and informed consent form will be available from ICMR and Zydus Lifesciences Limited upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe following individuals are employed by and have affiliations with the organizations listed: - MG, GK, SR, SK, and AM: Indian Council of Medical Research (ICMR), co-funder of the study. DP, KK, and SS: Zydus Lifescience Limited, co-funder of the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMehanna AS. Sickle cell anemia and antisickling agents then and now. Cur Med Chem. 2001;8(2):79\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSundd P, Gladwin MT, Novelli EM. Pathophysiology of sickle cell disease. Annu Rev Pathol Mech Dis. 2019;14:263\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePlatt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358(13):1362\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWare RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 2010;115(26):5300\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMatte A, Zorzi F, Mazzi F, Federti E, Olivieri O, De Franceschi L. New therapeutic options for the treatment of sickle cell disease. Mediterr J Hematol Infect Dis 2019; 11(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDhillon S, Desidustat. First Approval Drugs. 2022;82(11):1207\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJanssens LK, Stove CP. Sensing an oxygen sensor: development and application of activity-based assays directly monitoring HIF heterodimerization. Anal Chem. 2021;93:14462\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, et al. Phase I clinical study of ZYAN1, a novel prolyl-hydroxylase (PHD) inhibitor to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers. Clin Pharmacokinet. 2018;57:87\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eParmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Investigators T et al. 2019. Outcomes of desidustat treatment in people with anemia and chronic kidney disease: a phase 2 study. Am J Nephrol. 2019;49(6);470\u0026ndash;478.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGang S, Khetan P, Varade D, Chinta VR, Mavani S, Gupta U, et al. Study Investigator Group. Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D). Am J Nephrol. 2022;53(5):343\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJoharapurkar A, Pandya V, Patel H, Jain M, Desai R. Desidustat: a novel PHD inhibitor for the treatment of CKD-induced anemia. Front Nephrol. 2024;22:4:1459425.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rare Disease, Desidustat, Hemoglobin, Sickle cell disease, HIF-PHI","lastPublishedDoi":"10.21203/rs.3.rs-6911159/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6911159/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/em\u003eSickle cell disease (SCD) is a genetic disorder characterized by chronic hemolysis and vaso-occlusive crises. Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), has shown promise in treating SCD by stimulating erythropoietin production in a similar manner that happens in response to hypoxia, promoting erythropoiesis and improving iron metabolism leading to increased hemoglobin and RBC indices.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis is a Phase IIa, double-blind, randomized, placebo-controlled, parallel-group, proof-of-concept, multicenter clinical trial designed to evaluate the efficacy and safety of Desidustat in Indian adults with sickle cell disease (SCD). A total of 24 participants will be enrolled based on predefined eligibility criteria, with 8 subjects per dose cohort (50 mg, 100 mg and 150 mg), randomized in a 3:1 ratio (Desidustat: Placebo). The study includes a screening period of up to 4 weeks, an 8-week treatment phase, and a follow-up visit at Week 10, totaling 98 days. Efficacy (hemoglobin response rate) will be assessed at Week 8 relative to baseline compared to placebo. Dose adjustment of Desidustat at week 4 will be guided by hemoglobin levels measured using a calibrated HemoCue instrument.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eDiscussion:\u003c/strong\u003e\u003c/em\u003eManagement of sickle cell disease (SCD) has limited treatment modalities available like hydroxyurea and blood transfusions. They offer benefits but their limitations underscore the ongoing need for safer, more effective, and accessible treatments. This proof-of-concept trial will investigate the efficacy and, safety of Desidustat oral tablet, 3 times per week for 08 weeks in SCD patients. Results from this trial could aid in establishing a cost-efficient therapeutic option for managing rare disease like SCD.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e\u003c/em\u003e The study is approved and is being conducted for new drug as per the GCP guideline of Central Drugs Standard Control Organization (CDSCO), CT NOC number is CT/SND/27/2023 with protocol number DESI.23.001, Version No. 01 Registered on 12 June 2023.\u003c/p\u003e","manuscriptTitle":"Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Desidustat Oral Tablet in Sickle Cell Disease: A Phase IIa Proof-of-Concept Evaluation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-16 01:59:44","doi":"10.21203/rs.3.rs-6911159/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-10-02T16:34:01+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-02T14:25:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-15T05:55:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-07-14T05:05:49+00:00","index":"","fulltext":""},{"type":"decision","content":"Major revision","date":"2025-07-07T06:32:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5bf7ce8e-7eea-4259-9dd4-8e4e1c84e120","owner":[],"postedDate":"October 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T11:58:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-16 01:59:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6911159","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6911159","identity":"rs-6911159","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}