German Clinical Trials Register

Acronym/abbreviation of the study

BetHaem2012

URL of the study

No Entry

Brief summary in lay language

Patients with haemophilia A suffer from a deficiency of coagulation factor VIII due to different mutations in the factor VIII gene resulting in an increased bleeding risk. In some patients certain point mutations (so called missense mutations) lead to the misfolding of the factor VIII protein in the producing human cells. The misfolded factor VIII is retained in the cells and not secreted into the blood. Therefore these patients have reduced factor VIII blood levels. In preclinical investigations the amino acid derivative betaine could restore the folding and secretion of such misfolded factor VIII proteins and increase the factor VIII levels in blood. Therefore this clinical trial should investigate the effect of oral betaine intake on factor VIII activity and other coagulation parameters in haemophilia A patients. Up to 30 patients with mild to moderate haemophilia A will be included in the trial provided that they have a confirmed factor VIII missense mutation and do not need factor VIII substitution regularly. We hypothesize that an oral betaine therapy could help to increase the factor VIII blood levels in these patients. In the clinical trial the active substance betaine (trade name Cystadane®) will be compared with placebo. Participating patients receive betaine as well as placebo to better prepare the betaine-specific effects. One patient group receives the study medication betaine (3 g/twice daily) for 15 days first. After 7 days without any intake of medication patients switch to placebo intake for additional 15 days. The other patient group starts with placebo intake and switches after the break to betaine. Medication order for each patient will be decided by a random process. The study is also single-blinded, that means the patient does not know, if he just receives betain or placebo. To investigate betaine effects, 16 visits to Hämophiliezentrum Frankfurt for blood sampling will be necessary. In the laboratory factor VIII levels and coagulation parameters in the blood as well as safety parameters will be determined.

Brief summary in scientific language

Haemophilia A is a X-chromosome linked hereditary bleeding disorder characterized by decreased plasma levels of factor VIII and can be caused by different mutations in the factor VIII (FVIII) gene. Missense mutations often lead to misfolded FVIII proteins which are mostly intracellularly retained in the endoplasmic reticulum and degraded. The FVIII transport and secretion out of the producing cell is impaired, but the functionality of the coagulation protein is still retained. Affected patients show residual FVIII activity levels in blood plasma. So called chemical chaperones have the potential to stabilize the native conformation of intracellular proteins. Thereby they can restore the processing and secretion of misfolded proteins. Preclinical studies have recently shown that the osmolyte betaine functions as chemical chaperone and can increase the secretion efficiency of FVIII proteins with missense mutations in vitro and in vivo (Roth et al., 2012). Betaine as Cystadane® has already been EMA-designated for the indication of Hyperhomocystenemia and will be used in another indication in this study. We hypothesize that the rescue of trafficking-defective FVIII by betaine could be used as a therapeutic concept to enhance the folding, processing and secretion of FVIII in patients with haemophilia A. A final increase of FVIII plasma level could reduce the bleeding risk in these patients Eligible are patients with mild to moderate haemophilia A due to a confirmed missense mutation in the FVIII gene without need for regular factor substitution prophylaxis. This study is designed as a single-blind, randomized, 2-armed, placebo-controlled cross-over study and it is planned for the next two years. It should include 30 patients. Each patient will be enrolled for 40 days. The patients will be divided into two arms. Arm 1 receives two daily oral doses betaine (Cystadane®, 2x3 g) for 15 days and after a washout period of 7 days placebo for 15 days. Arm 2 receives placebo first. Primary objective is the effect of betaine on FVIII activity levels in plasma, measured by an one and two stage assay. Secondary further coagulation parameters as well as safety parameters will be investigated. Final study aim should be to prove if regular betaine intake changes FVIII activity levels and could be an oral therapy option for haemophilia patients with missense mutations.