Comparison of 7 day vs 14 day treatment of Primaquine for Plasmodium vivax malaria

Phase 3

Active, not recruiting

Conditions: Plasmodium vivax malaria without complication,

Registration Number: CTRI/2022/12/048283

Lead Sponsor: ICMR National Institute of Malaria Research

Brief Summary: *Plasmodium vivax* malaria is an important public health concern. In 2020, the WHO Southeast asia region reported 2% of the global malaria burden and India shouldered 83% of the cases in the region. Although the Southeast asia region have reported a 75% reduction in malaria deaths from 35000 in 2000 to 9000 in 2020, India accounted for 82% of these deaths; a large number for a curable disease.1 Out of the total 1,90,000 malaria cases reported in India in 2020, 70,000 were caused by *P. vivax*. *P. vivax* infections prove to be a substantial challenge for malaria control and elimination targets because of the ability of *P. vivax* to cause relapse infections. Relapse results from activation of dormant liver stages (hypnozoites) and can occur weeks or months following an acute infection. Recurrent infections are usually associated with a febrile illness, a cumulative risk of severe anaemia, direct and indirect mortality, and these relapses are the most important source of onward transmission of the parasite. The only hypnozoitocidal (capable of clearing the intra-hepatic schizonts and hypnozoites of *P. vivax*) drug that is widely available and licensed for use for *P. vivax* radical cure regimens in India is primaquine (PQ). PQ is an 8-aminoquinoline compound with the potential of causing severe drug-induced haemolysis in glucose-6-phosphate-dehydrogenase (G6PD) deficient patients and has to be given with caution. The Indian National Center for Vector Borne Diseases Control (NCVBDC) recommends a radical cure regimen comprising of 0.25 mg/kg body weight for 14 days equivalent to a total dose of 3.5 mg/kg. PQ has a narrow therapeutic index and a short elimination half-life of about 4-7 hour.2 Thus, PQ requires daily administration for up to 2 weeks for optimum action but this may result in poor compliance. This poor compliance may increase the chances of relapse occurring after weeks, months, or years.3 The current regimen poses the problems of low adherence and reduced effectiveness because of long duration, hence there is a need to reconsider and evaluate a higher daily dose. The daily dose however is limited by the potential risk of hemolysis and tolerability. The treatment can be given over 7 days at 0.50 mg/kg body weight, so that the total dose remains the same. This prospective clinical study is proposed to compare and evaluate the efficacy of two radical cure regimens in the treatment of *P. vivax* malaria in India.

1. World Malaria Report 2021. Available on <https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021> Accessed on 13th March 2022

2. Saravu K et al.A pilot randomized controlled trial to compare the effectiveness of two 14-day primaquine regimens for the radical cure of vivax malaria in South India. Malaria journal.2018;17(1):1-11

3. Fernando, D., C. Rodrigo, and S. Rajapakse, *Primaquine in vivax malaria: an update and review on management issues.* Malaria journal.2011;10(1):1-12.

Detailed Description: Not available

Recruitment & Eligibility

Status: Closed to Recruitment of Participants

Sex: All

Target Recruitment: 400

Inclusion Criteria

1.P. vivax (asexual) malaria monoinfection confirmed by microscopy on a thin and thick blood smear 2.Age 16 years and over of either gender.
3.Fever > 37.5Â°C axillary, or a history of fever within 48 hours 4.Female patients of child-bearing potential are included if they are non-lactating and willing to use contraceptive methods during the study period.
Non-child bearing potential defined as: 4.1 post-menopausal (12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL), pre-menopausal and has had a hysterectomy or a bilateral oophorectomy (removal of the ovaries) or a bilateral tubal ligation with medical report verification or, 4.2 Child-bearing potential, has a negative urine pregnancy test at screening, and agrees to comply with one of the following during the treatment stage of the study and for a period of 90 days after stopping study drug: 4.2.1 Use of oral contraceptive, either combined or progesterone alone (if no contraindications to oral contraceptives exist).
4.2.2 Barrier contraceptive if oral contraceptives are contraindicated 4.2.3 Use of an intrauterine device.
5.Willing to give informed consent.
6.Willing to comply with protocol instructions and duration of follow up.
7.Only patients living in and around the site facilities will be enrolled in the study to facilitate follow-up.

Exclusion Criteria

1.Patients with G6PD activity less than 30% of the adjusted male median (AMM), tested by UV spectrophotometry.
2.Patients with mixed infection with P.
vivax and P.
falciparum (e.g. identified by Giemsa-stained smear or rapid diagnostic test).
3.Patient with body weight less than 40 kg.
vivax malaria defined as per Indian National Guidelines criteria (Appendix I).
5.Haemoglobin <8 g/dl to be measured by Hb auto analyser.
6.Cannot tolerate oral treatment 7.History of haemolytic anaemia or methemoglobinemia or blood transfusion within 90 days 8.Pregnant and lactating females.
9.Known allergy to chloroquine, primaquine or any other related drugs.
10.Evidence of gastro-intestinal dysfunction that could alter absorption or motility (e.g., diarrhoea defined as >3 episodes of watery stools in the previous 24 h or patients who have had three episodes of vomiting within 24 h prior to screening).
11.Use of concomitant medications that could induce haemolysis or haemolytic anaemia or depressants of myeloid element of the bone marrow.
12.Any anti-malarial treatment taken 1 month prior to enrolment.
13.Ongoing prophylaxis with drugs having anti-malarial activity 14.Participation in any other investigational drug study of at least 3 months prior to screening 15.Any other underlying disease that could compromise the diagnosis and the evaluation of the response to the study medication (including clinical symptoms of immunosuppression, HIV, Hepatitis, tuberculosis, Splenectomy conducted earlier as confirmed by history or clinical examination; evidence of clinically significant cardiovascular, pulmonary, metabolic, gastrointestinal, neurological, or endocrine diseases, malignancy, or other abnormalities.
16.Retinal/visual field defects or auditory defects and history of psoriasis and porphyria.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
â€¢The incidence risk of symptomatic P. vivax malaria	Month 6

Secondary Outcome Measures

Name	Time	Method
The incidence risk of any (symptomatic and asymptomatic) P. vivax malaria	Day 28, till month 6
The proportion of patients vomiting their medication	Within 1 hour of administration
The proportion of adverse events and serious adverse events	throughout study period
Risk of greater than 25% fall in haemoglobin on any day of treatment	throughout study period
Gastrointestinal (GI) tolerability - incidence of abdominal pain, heartburn, diarrhoea, constipation, nausea and vomiting	throughout study period
Ophthalmic safety - incidence of corneal deposits, retinal and visual field abnormalities.	throughout study period
The incidence risk of severe anaemia (Hb 8g/dl) and/ or the risk of blood transfusion	throughout study period

Trial Locations

Locations (3): Ahmedabad Municipal Corporation Hospital
🇮🇳
Ahmadabad, GUJARAT, India
Calcutta National Medical College and Hospital
🇮🇳
Kolkata, WEST BENGAL, India
ICMR-National Institute of Malaria Research
🇮🇳
West, DELHI, India
Ahmedabad Municipal Corporation Hospital
🇮🇳Ahmadabad, GUJARAT, India
Dr KJ Upadhayay
Principal investigator
9825362253
drkjupadhyay@hotmail.com
Dr Rajendra Kumar Baharia
Principal investigator
7726986307
rajendrabaharia@gmail.com