Evaluating the safety, tolerability, pharmacokinetics and efficacy of clofazimine in cryptosporidiosis (CRYPTOFAZ): study protocol for a randomized controlled trial

Abstract

Background: Cryptosporidium infection and diarrhea (cryptosporidiosis) is a life-threatening infection in persons with HIV and also in children of 6-18 months of age in the developing world. To date, only nitazoxanide is licensed for treatment of cryptosporidiosis, and only in persons after the first year of life and with healthy immune systems. Clofazimine (CFZ: Lamprene®), an established drug that has been used for leprosy for more than 50 years, recently has been described as effective against Cryptosporidium in vitro and in mouse infections. The efficacy and pharmacokinetics of CFZ in vivo, in HIV-infected patients with cryptosporidial diarrhea are not known.

Methods: CRYPTOFAZ includes a randomized, double-blind, placebo-controlled study of the safety, tolerability and Cryptosporidium inhibitory activity of orally administered CFZ in subjects with HIV infection and chronic diarrhea with Cryptosporidium. An additional open label aspect of the study will compare the pharmacokinetics (PK) of orally administered CFZ in HIV-infected individuals with and without Cryptosporidium-associated diarrhea. The study will recruit a total of 66 subjects. Study participants will be given either CFZ or a placebo for 5 days while in hospital and will be followed up after discharge. Cryptosporidium will be diagnosed by quantitative PCR as the definitive test and by stool ELISA, which will also be used to quantify the shedding of Cryptosporidium in stool. PK will be studied on plasma and stool samples. Primary endpoints include reduction in the number of Cryptosporidium shed in stools over a 5-day period and compared to placebo recipients and the PK of CFZ in plasma assessed by area under the curve, peak plasma concentration, and half-life (T ½) determined after the last dose.

Discussion: This study provides an opportunity to explore a possible treatment option for HIV-infected patients with cryptosporidial diarrhea, who, as of now in Malawi and most of sub-Saharan Africa, do not have a definitive treatment apart from supportive care. The strength of this study lies in it being a randomized, double-blind, placebo-controlled trial. If shown to be effective and safe, the findings will also lay a foundation for a future study of the use of CFZ in children 6-18 months of age.

Trial registration: ClinicalTrials.gov, NCT03341767 . Registered on 14 November 2017.

Keywords: Clofazimine; Cryptosporidium; Diarrhea; HIV; Immunosuppression; Lamprene.

Conflict of interest statement

Ethics approval and consent to participate

Written informed consent by the participants older than 18 years of age will be obtained from the participants’ guardians if they are illiterate. The trial was approved by NHSRC (reference 17/05/1821) on 28 July 2017, and by the Liverpool School of Tropical Medicine Research Ethics Committee (reference 17–031) on 15 November 2017. The University of Washington did not require additional approval. Approval for conducting the clinical trial and for importation of the study investigational products was obtained from PMPB (28 November 2017; reference PMPB/CTRC/2A/CFZ-001).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Schematic diagram for study enrollment and conduct. RDT, Cryptosporidium rapid diagnostic test; IP, investigational product; PK, pharmacokinetics

Fig. 2

Summary of study events schedule. RDT, Cryptosporidium rapid diagnostic test; ECG, electrocardiogram; AEs, adverse events; GI, gastrointestinal; IP, investigational product; ELISA, enzyme-linked immunosorbent assay; CFZ, clofazimine; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Alk Phos, alkaline phosphatase