Single Dose, Two-stage Bioequivalence Study of SCMC-Lys Salt 1.35 g Powder vs SCMC-Lys Salt 90 mg/mL Syrup
Condition: Bronchitis
MeSH terms: Bronchitis
Study type: Interventional
Phase: Phase 1

Summary: 
      To investigate the bioequivalence between two formulations containing
      S-carboxymethyl-L-cysteine L-lysine monohydrate salt (SCMC-lys) when administered as single
      oral dose in two consecutive study periods to healthy male and female volunteers under
      fasting conditions.
    

Detailed description: 
      As a part of the Dompé farmaceutici S.p.A. extension line program, Dompé developed a new 1.35
      g powder for oral solution formulation of carbocysteine L-lysine salt-monohydrate.

      The present bioequivalence phase I study is needed to compare the bioavailability and the
      concentration-time profile of the new 1.35 g powder for oral solution formulation with the
      reference compound Fluifort® 90 mg/mL syrup (15 mL corresponding to 1.35 g of SCMC- lys).

      The new 1.35 g powder for oral solution formulation of carbocysteine L-lysine salt-
      monohydrate is expected to be bioequivalent to Fluifort® 90 mg/mL syrup with the same
      indications: mucolytic, expectorant in acute and chronic respiratory tract disorders.

      Primary end-point is to evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of
      absorption of carbocysteine after single oral administration of test and reference.

      Secondary end-point are:

        1. To describe the pharmacokinetic (PK) profile of carbocysteine after single oral
           administration of test and reference;

        2. to collect safety and tolerability data after single oral administration of test and
           reference.

      Study Design:

      The trial has been designed in agreement with the "Guideline on the investigation of
      bioequivalence." Due to the lack of information about the PK profile of the new formulation
      it was decided to use a "two stage" bioequivalence study design, that allows a re-calculation
      of the sample size in case the number of subjects initially enrolled in the study is not
      large enough to provide a reliable answer to the questions addressed due to underestimation
      of the variability or misleading estimation of the point estimate for the T/R ratio of the
      geometric means.

      The sample size of stage 1 was calculated assuming a point estimate for the T/R ratio of the
      geometric means of 1.053 (i.e. μR=0.95·μT) and a multiplicative coefficient of variation
      (CVm) of 20% for both AUC0-t and Cmax. A power of 90% was considered and, according to the
      Pocock spending function and to the current European bioequivalence guideline, the α level
      was set to 0.0294. Fifteen (15) subjects per sequence (i.e. 30 subjects overall) will be
      enrolled in the first stage of the study.

      After the end of study stage 1, PK parameters will be calculated and an ad interim
      bioequivalence test will be performed on the calculated PK parameters Cmax, AUC0-t and
      AUC0-∞. To safeguard the overall type I error, the α level of the bioequivalence test will be
      set to 0.0294 according to the Pocock spending function. Should bioequivalence be proven with
      the results of the subjects of the first stage, the primary objective of the study would then
      be satisfied and the second study stage will not take place. Should bioequivalence not be
      proven with the results of the subjects of the first stage and with an a posteriori
      calculated power > 90% for both AUC0-t and Cmax, the study will be stopped and the
      bioequivalence will not be proven.

      Should bioequivalence not be proven with the results of the subjects of the first stage and
      with an a posteriori calculated power ≤ 90% for AUC0-t or Cmax, the overall sample size for
      the study (stage 1 plus 2) will be calculated on the basis of the ad interim bioequivalence
      results. The additional subjects will be enrolled into the second study stage. After
      completion of stage 2, the PK analysis and the bioequivalence test will be performed on the
      pooled subjects of the two study stages. The α level of the bioequivalence test of stage 1
      plus 2 will be set to 0.0294 according to the Pocock spending function. The second stage will
      be performed after notification of the sample size to the local Ethics Committee and to the
      central Swiss authority (Swissmedic).
    

Intervention name(s): 1.35 g SCMC- lys powder; Fluifort® syrup
Intervention type(s): Drug; Drug
Intervention description(s): 1.35 g SCMC- lys powder for oral solution; SCMC-lys Syrup 90 mg/ml
Other intervention name(s): Carbocisteine lysine salt 1.35 g powder for oral solution; Carbocisteine lysine salt 90 mg/ml syrup
Intervention MeSH terms: Carbocysteine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment