Naturlose (D-Tagatose) Efficacy Evaluation Trial
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this trial was to evaluate the effectiveness and safety of Naturlose
      (Tagatose) for glycemic control in people with Type 2 diabetes who were not taking other
      medications for the condition and who were under diet control and exercise.

      The study lasted approximately one year. HbA1c was monitored every 2 months after entry into
      the study. Safety and tolerance for tagatose were assessed every 2 months throughout the
      study. A total of 14 visits were made to the study site.
    

Detailed description: 
      This was a Phase 3, prospective, randomized, double-blind, placebo-controlled, multicenter
      clinical trial to evaluate the efficacy, safety, and tolerability of D-tagatose (as compared
      to placebo). Prior to the start of treatment, subjects participated in an 8-week run-in
      period during which diabetes education was provided and diet and exercise treatment
      stabilized. Efficacy analyses were conducted on data from 4 and 6 months.

      Screening Visit

      Based on the inclusion and exclusion criteria, eligible subjects underwent a basic physical
      examination, pregnancy test for females, and hematology, clinical chemistry, and urinalysis
      tests. Basic physical examination included physical measurements, general examination by
      observation, palpation, percussion, auscultation, blood pressure measure, and heart rate
      check. The clinical laboratory tests included: 1) hematology (hematocrit, hemoglobin, MCH,
      MCHC, MCV, total white blood cells, platelets, and differential); 2) clinical chemistry
      (sodium, chloride, potassium, CO2, BUN, uric acid, albumin, creatinine clearance, SGOT, SGPT,
      bilirubin (total and direct), phosphorus, calcium, alkaline phosphatase, total protein, and
      glucose (fasting); 3) HbA1c; 4) serum lipid profile including total cholesterol, HDL, LDL,
      and triglycerides; 5) urinalysis (appearance, volume, specific gravity, pH, glucose, protein,
      and microscopic evaluation of urinary sediment).

      Run-in Period

      Subjects deemed potentially eligible on the basis of their medical records were to continue
      on their previously established diet and exercise treatment program under physician's
      recommendation for 8 weeks. Patients were to record their food intake and exercise in
      nutrition diaries.

      Treatment Period

      The treatment period consisted of 12 monthly visits, the first of which was used to gather
      the baseline data for the efficacy and safety parameters and also included the first
      distribution of test and placebo treatments. Subjects who received study drug for more than 6
      months were evaluated for safety and efficacy the first 6 months and then for safety only
      thereafter.

      Baseline and Distribution of Test and Placebo Treatments

      Approximately 550 enrolled subjects were to be randomized into the study. Subjects were
      randomized to one of the two treatments in a 1:1 ratio. Each eligible subject was randomized
      to a group assignment on the basis of a randomly generated number. Randomization was
      stratified by the screening HbA1c values (<7.5% and ≥7.5%) to ensure an even distribution of
      subjects between the two treatments. Randomization was to take place through an Integrated
      Web-based Randomization System (IWRS) which sites accessed in order to make randomized
      treatment assignments.

      After the 8 weeks run-in period, subjects returned (Visit 2) to the study sites and underwent
      medical history review, and the same examination and clinical laboratory tests as those
      performed during the screening visit. In addition, subjects received their randomized study
      treatment and detailed instructions about its use.

      There were two treatment groups in this trial: 1. Drug (D-tagatose), and 2. Placebo
      (Splenda). The dose of tagatose was 15 g in solution in a final volume of approximately 4
      ounces of water (~250 mL) taken 3 times daily (tid); the dose of placebo (Splenda) was to be
      1.5 g.

      Treatments were dispensed by an unblinded staff member who had no other role in the trial;
      all other clinical center staff were blinded to treatment. If the patient was outside the +/-
      7 day window, the investigator/site staff would document the information in the subject chart
      and provided the Sponsor with a note to file.

      Procedures Visits

      Every other month after Visit 2 subjects returned to the study site and underwent the same
      comprehensive testing that they underwent at Visit 2. Drug and dietary compliance was to be
      verified by sachet counts at each visit and by nutritional diaries.

      DATA QUALITY ASSURANCE

      A study initiation meeting was held at each investigative site before enrollment of the first
      subject to review study design, study procedures, data collection, and investigator
      responsibilities. During interim field monitoring visits, the monitor verified CRF entries
      against available source documents and ensured that appropriate data were collected and
      documented. Independent GCP audits of selected study sites were performed. Prior to data
      entry, CRFs were checked for completeness and consistency by a monitor and verified against
      source documentation that was maintained at each study site. Data from CRF were reviewed and
      queries to the study sites were generated by the clinical and data management staff of the
      CRO. Discrepancies were reconciled with the study site and the respective laboratory.

      Prior to data lock a final audit report and memo was generated summarizing the audit findings
      and given to the Data Manager Data analyses were performed primarily with Statistical
      Analysis System (SAS®) software, version 9.2. SAS analysis datasets were crosschecked against
      the locked database and/or CRF. Data summary tables were crosschecked against SAS analysis
      datasets. All identified inconsistencies were reported to the lead statistician and resolved
      prior to production of this report. This clinical study report was checked for accuracy and
      consistency before sign-off.

      Statistical and Analytical Plans Amarex LLC, Germantown, MD prepared a statistical analysis
      plan (SAP) for the efficacy and safety data before database lock.

      Analysis Populations

      Intent-to-Treat Population

      The intent-to-treat (ITT) population was defined as all randomized subjects who received at
      least one dose of double-blind study medication and had a least one post-treatment visit
      evaluating efficacy. The ITT population was used for the main efficacy evaluation.

      Per Protocol Population

      The per protocol (PP) population was defined as all subjects in the ITT population who had
      80% compliance with medication for 75% of the dosing time points and who had no major
      protocol violations or eligibility violations.

      Safety Population

      The safety population consisted of all randomized subjects who received at least one dose of
      double-blind study medication and had at least one post treatment visit evaluating safety.
      This population was used for all of the safety analyses.

      Handling of Duplicate, Missing and Outlier Data

      For data that were identified by the Sponsor's Medical Monitor as clinical outliers, two
      separate analyses were conducted, one including the outlier and one from which the outlier
      was excluded. The impact of all possible combinations of the outliers was to be treated in
      the context of the parameter. For the ITT population, missing data (including missing values
      at intermediate visits) were imputed from scheduled visits using the
      last-observation-carried-forward (LOCF) method. A blind review of the data was conducted
      prior to statistical analysis to determine data accuracy. Safety data were compiled on all
      subjects without exclusion, and in the case of AEs, the relationship to study product was
      made. The determination that a subject was to be excluded from an analysis population was
      jointly made by the sponsor and the investigator in the blind review meeting.

      Covariates, Stratification Factors, and Subgroups

      To improve the precision of the analysis, covariate analyses were conducted. The respective
      baseline values were used as covariates in the analysis models for all the continuous
      variables; along with the pre-specified stratification factor, screening HbA1c values (<7.5%
      and ≥7.5%). The adjusted least squared (LS) means at each time point were reported. Other
      clinically meaningful baseline covariates and stratification factors were examined; if
      statistically significant, these factors were included in the analysis models.

      Interim Analyses

      Two blinded interim analyses (IAs) were planned, one when approximately 40% of subjects had
      been randomized and completed through month 6, and the other when over 60% of the subjects
      had been randomized and completed through month 6. The ITT population was used for the
      analyses conducted in each IA. The IA was directed and conducted by an independent
      statistician, who was not involved in the trial conduct other than this IA. The main purpose
      of the IAs was to assess the assumption made concerning the standard deviation in the sample
      size calculation for the primary end-point (mean change in HbA1c). Two such IAs were planned
      because the trial started earlier in the USA than in India, so the first IA was more likely
      to reflect the results from the USA population, while the second IA was more likely to
      reflect the results from the India population. For each IA, the independent statistician used
      the blinded data, the observed pooled standard deviation, and the other original assumptions
      noted in the sample size determination (e.g. Power, Type I error rate) to recalculate the
      sample size. Based on the documented sample size re-calculation and the observed dropout
      rate, the intent was that the independent statistician could recommend a new, larger sample
      size to the sponsor; however, in neither IA was this necessary.

      Statistical Methods Subject Characteristics

      The subject population enrolled in this trial was characterized according to

        -  the disposition of subjects within the trial;

        -  the demographics, baseline clinical laboratory assessments, and previous and concomitant
           medical history;

        -  concomitant medications; and

        -  treatment duration and compliance characteristics.

      Demographic and baseline characteristics were summarized and also provided as data listings.
      Continuous data variables were summarized according to the number of observations, mean,
      standard deviation, median, and minimum and maximum values, while categorical data variables
      were summarized according to frequency counts and percentages.

      Treatment duration and compliance characteristics were summarized by treatment group and
      analysis population with the duration of dosing (days) being calculated as date of last dose
      minus date of first dose plus 1. Percent compliance was calculated as [(total units of drug
      returned minus the total units of drug dispensed) divided by the total dispensed] times 100%.

      Efficacy Analyses

      Statistical tests for the efficacy analyses were to be two-sided, with no p-value adjustment,
      and were to focus on the responses of the ITT population with the PP population being used in
      supportive analyses. To assess the primary end-point of change in HbA1c level from baseline,
      the general linear model (analysis of covariance) adjusted for baseline and important
      stratification factors, e.g., baseline HbA1c and site, was used. In this analysis, in order
      to protect the statistical degrees of freedom, sites were pooled according to location and
      other factors. The closed test procedure was to be used for the secondary end-points in order
      protect the Type I Error rate of α = 0.05. For this procedure, the secondary end-points were
      to be analyzed in the following order: 1. Body Mass Index 2. Triglycerides 3. LDL 4. Total
      cholesterol 5. Fasting blood glucose 6. Proportion of subjects achieving HbA1c <7% and/or
      ≤6.5% 7. Insulin 8. HDL
    

Intervention name(s): Tagatose; Sugar Substitute Splenda
Intervention type(s): Drug; Drug
Intervention description(s): powder; 15 grams three times daily; one year; 1.5 g powder tid
Other intervention name(s): Naturlose
Intervention MeSH terms: Tagatose
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment