Low Dose Emicizumab vs Low Dose Factor VIII in Prophylaxis in Hemophilia A Patients

Official title

Comparison of Low Dose Emicizumab and Low Dose Factor VIII as a Prophylaxis in Hemophilia A Patients- a Randomized Control Trial'

Overview

Low dose factor VIII prophylaxis is practiced around the world. Role of standard dose Emicizumab prophylaxis is well established. Emicizumab is an expensive drug. Standard dose Emicizumab prophylaxis is very expensive for hemophilia A patients and troublesome for government to ensure continuous supply. This study intends to compare low dose Factor VIII prophylaxis with low dose Emicizumab prophylaxis and compare whether low dose Emicizumab is as effective as low dose Factor VIII prophylaxis. So, it is possible to continue prophylaxis program in hemophilia A patients with a cost-effective way in our country without risking the patient health. Moreover, Emicizumab prophylaxis reduces the chance of developing inhibitor to Factor VIII and it is convenient for administration due to less frequent and subcutaneous administration. 20 severe hemophilia A patients will be selected randomly from interested patients for this study. 6 patients with inhibitor will be randomized in Low dose Emicizumab with Inhibitor group (I) and rest 14 will be randomized by block randomization in Low dose Emicizumab (without inhibitor-WI) and low dose Factor VIII group at 4:10 ratio. Initial loading dose will be given and the participants will be followed up for 6 months. At the end of the study Annualized bleeding rate (ABR), Annualized joint bleeding rate (AJBR), Annualized spontaneous bleeding rate (ASBR), APTT will be compared among the groups. Inhibitor to factor VIII will also be evaluated after six months in Factor VIII group.

Detailed description

Selection criteria for the study- Severe hemophilia A patients with or without inhibitor to factor VIII will be eligible to participate in the study. Patients with inhibitor will not be included in factor VII group.

Sample Size: Sample size is determined by availability of drugs rather than any scientific formula. The investigators can provide Emicizumab to 10 patients for 28 weeks as prophylaxis. So, the investigators intend to include 10 patients in each group.

Sampling technique: The investigators will select 20 severe hemophilia A patients randomly from interested patients. The investigators will randomize 6 patients with inhibitor in Low dose Emicizumab with Inhibitor group (I) and rest 14 will be randomized by block randomization in Low dose Emicizumab (without inhibitor-WI) and low dose Factor VIII group at 4:10 ratio Variables to be studied- A. Independent variable

1. Socio-demographic variables- Age, Educational status, Weight, Occupation 2. Variables related to Hemophilia- Presence of Inhibitor B. Dependent variable

1\. Main outcome variables- Annualized bleeding rate (ABR), Annualized joint bleeding rate (AJBR), Annualized spontaneous bleeding rate (ASBR), APTT 2. Confounding variables- Development of new inhibitor to factor VIII Patients and/or parents will be thoroughly informed about the study, drugs to be used, risk \& benefits and follow up plan. Their consent for this study will be taken and they will be enrolled in the study. For Participants under 18 years, consent will be obtained from parents or legal guardian. Participants ≥18 years will give his/her own consent. Randomization will be generated by computer.

Dose- Emicizumab 0.8-1.5mg/kg weekly for 4 weeks as loading dose. Then 0.8-1.5mg/kg 4-weekly for 24 weeks. Inj. Emicizumab has 30mg in vail. Dose will be rounded to 30mg, 60 mg or any dose nearest to 1 mg/kg when fractionation of vail is possible.

Factor VIII- 10-15 unit/Kg thrice weekly (for conventional half-life products) or twice weekly (for extended half-life products) for 28 weeks. Inj. Factor VIII is available in 250U, 500U, 750U \& 1,000 IU vail sizes. Dose will be round up to full nearest full vail strength.

Follow Up- Participants in Emicizumab group will visit weekly for first 4 week than once in every 4 week for 24 weeks (Total 28 weeks).

Participants in Factor VIII group will visit twice weekly for 28 weeks. Information of data collection sheet will be collected once in a week.

Patient must attend physically for every dose administration. He will be asked for number of bleeding- traumatic, spontaneous bleeding, joint bleeding, frequency of hospital visit due to hemophilia related problems in between doses and investigate for APTT.

Primary End Point- This study will include 28 weeks follow up of the patients. Each patient will receive 28 weeks prophylaxis. After that period patients will continue prophylaxis if drugs are available but will not be considered for this study. Otherwise, they will receive on demand treatment in our HTC (hemophilia treatment center).

Supportive care and rescue- A Data and Safety Monitoring Board (DSMB) will be formed which will include members suggested by IRB. Any adverse event or serious adverse event (will be delt with proper medical care.

If any patient developed spontaneous or traumatic bleeding episode during prophylaxis, they will be treated with standard dose on demand treatment on priority basis.

Interventions

• Drug Emicizumab Injection
  Emicizumab 0.8-1.5mg/kg weekly for 4 weeks as loading dose. Then 0.8-1.5mg/kg 4-weekly for 24 weeks will be used in Emicizumab group-I and Emicizumab Group- WI
• Drug Factor VIII (FVIII)
  10-15 unit/Kg thrice weekly (for conventional half-life products) or twice weekly (for extended half-life products) for 28 weeks. Inj. Factor VIII is available in 250U, 500U, 750U \& 1,000 IU vail sizes. Dose will be round up to full nearest full vail strength.

Primary outcome measures

• Mean of Annualized bleeding rate (ABR) among the study groups will be compared. [Time frame: 06 months]
• Mean of Annualized joint bleeding rate (AJBR) among the study groups will be compared. [Time frame: 06 months]
• Mean of Annualized spontaneous bleeding rate (ASBR) among the study groups will be compared. [Time frame: 06 months]
• Mean of APTT among the groups will be compared. [Time frame: 06 months]

Secondary outcome measures (1)

• Inhibitor to Factor VIII- [Time frame: 06 months]

Eligibility criteria

Inclusion criteria

• Severe hemophilia A patient with or without inhibitor to factor VIII.

Exclusion criteria

• 1\. Severe hemophilia A patient not willing to participate.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Bangladesh · 1 center

• Dhaka Medical College Hospital — Dhaka

Publications

• Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, Kasai R, Yoneyama K, Yoshida H, Nogami K. Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Adv. 2017 Sep 27;1(22):1891-1899. doi: 10.1182/bloodadvances.2017006684. eCollection 2017 Oct 10. PMID 29296836
• Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jimenez-Yuste V, Mahlangu J, Kruse-Jarres R, Wang M, Uguen M, Doral MY, Wright LY, Schmitt C, Levy GG, Shima M, Mancuso ME. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019 Dec 12;134(24):2127-2138. doi: 10.1182/blood.2019001869. PMID 31697801
• Xu Y, Wang Y, Wu R, Zheng C, Zhang L, Xu W, Feng X, Wang H, Cao X, He L, Xue T, Jin M, Xie B, Ling J, Sun L, Su R, Cheng H, Fang Y, Poon MC, Liu W, Zhang L, Xue F, Yang R. Reduced doses of emicizumab achieve good efficacy: Results from a national-wide multicentre real-world study in China. Haemophilia. 2024 Jul;30(4):959-969. doi: 10.1111/hae.15062. Epub 2024 Jun 9. PMID 38853005

Identifiers

NCT: NCT06938659 · ERC-DMC/ECC/2024/215

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗