Conditions: Post-acute COVID-19 Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 676
Healthy volunteers: no

Brief summary:
The multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial.

The objective of this study is to evaluate the efficacy and safety of Prospekta in the treatment of asthenia in patients after the coronavirus infectious disease (COVID-19).

Detailed description:
Design: the multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial.

The study will enroll adult patients of either gender aged 18 to 65 years after new coronavirus infection of 2019 (COVID-19) with symptoms of asthenia that appeared during or after an acute coronavirus infection (COVID-19) and persisting 4 to 12 weeks from the onset of coronavirus infection.

After the patient signs the patient information sheet and the informed consent form for participation in the study, complaints, medical history, physical examination, registration of vital signs are collected, the patient fills in the Fatigue Severity Scale (FSS) and Hospital Anxiety and Depression Scale (HADS). A six-minute walk test (6MWT) is carried out. The physician evaluates the severity of asthenia with FSS scale and records concomitant medications, co-morbidities and concurrent conditions.

If a patient meets all inclusion criteria and does not have any of the exclusion criteria at Visit 1 (Day 1), he/she is randomized to one of two groups: Group 1 - patients receive Prospekta at a dose of 1 tablet twice daily for 4 weeks; Group 2 - patients receive placebo on the study drug regimen.

The trial will use electronic patient diaries (EPD). The patient should record any possible deterioration (if applicable) in the EPD. At Visit 1 (Day 1), the physician will provide guidance on how to work with EPD, so that the patient can use it independently in the future.

At Visit 2 (Week 4 ± 3 days), the physician will collect patient's complaints, record physical examination data and vital signs as well as any changes in concurrent diseases and conditions. The patient fills out the FSS and HADS scales. A 6MWT is carried out. The physician monitors the prescribed treatment and use of concomitant medications, evaluates the safety of the study treatment and patient's compliance, filling out the diary.

The patient stops taking the study drug. At the end of the study treatment period, the patient is monitored for 4 weeks (follow-up period).

At Visit 3 (final visit, Week 8 ± 3 days), the physician collects patient's complaints, records physical examination data and vital signs, changes in concomitant diseases and conditions. The patient fills in the FSS and HADS scales. A 6MWT is carried out. The physician evaluates the safety of the study treatment, checks the completion of the diary.

During the study the patients are allowed to take medications for their chronic conditions, except for medicines listed as "Prohibited concomitant treatment".

Arms:
arm 1: Tablet for oral use. 1 tablet twice daily. The tablets are taken outside of meals (between meals or 15 minutes before eating or drinking), keep the tablets in the mouth, without swallowing, until completely dissolved. arm 2: Tablet for oral use. Placebo using Prospekta scheme.

Interventions: intervention 1: Prospekta intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration. intervention 2: Oral administration.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multicenter double-blind placebo-controlled randomized parallel-group 
clinical study of efficacy and safety of Prospekta in the treatment of patients 
with post-COVID-19 asthenia 
 
 
 
 
Phase III 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-MAP-006 
Version date: 
August 16, 2021 
ClinicalTrials.gov Id: 
NCT05074888 
 
 
 


Protocol No. MMH-MAP-006 
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Page 2 of 15 
Protocol Summary 
 
This document represents the protocol summary for the study on human subjects. The study will 
be carried out in accordance with ICH GCP, National Standard of the Russian Federation GOST 
52379-2005 "Good Clinical Practice", World Medical Association Declaration of Helsinki, 
relevant requirements of the regulatory authorities as well as the study procedures. 
Title of Study 
Multicenter double-blind placebo-controlled randomized parallel-group clinical study of efficacy 
and safety of Prospekta in the treatment of patients with post-COVID-19 asthenia 
Phase: III 
Sponsor: Company «MATERIA MEDICA HOLDING», Moscow, Russia 
Protocol No. MMH-MAP-006 
Objective of the study 
• To evaluate the efficacy of Prospekta in the treatment of asthenia in patients after the 
coronavirus infectious disease (COVID-19); 
• To evaluate the safety of Prospekta in the treatment of asthenia in patients after the coronavirus 
infectious disease (COVID-19).   
Endpoints  
Primary endpoint 
1. Change in the mean FSS score after 4 weeks of treatment. 
Secondary endpoints 
1. Change in the 6-minute walk distance after 4 weeks of treatment. 
2. Change in the severity of anxiety and depression as estimated by the HADS subscales after 4 
weeks of treatment. 
3. Change in the mean FSS score in the course of the 4-week follow-up. 
4. Change in the 6-minute walk distance in the course of the 4-week follow-up. 
5. Change in the severity of anxiety and depression as estimated by the HADS subscales in the 
course of the 4-week follow-up. 
6. Changes in vital signs after 4 weeks of treatment and in the course of the 4-week follow-up. 
7. Occurrence and nature of adverse events, their intensity (severity), causal relationship to the 
study drug, and outcome. 


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Safety assessment  
• Presence and nature of adverse events during the therapy, their intensity (severity), relation to 
the product, outcome. 
 
• Changes in vital signs. 
Study design  
Design – double blind placebo-controlled randomized parallel-group clinical study. 
The study will enroll adult patients of either gender aged 18 to 65 years after new coronavirus 
infection of 2019 (COVID-19) with symptoms of asthenia that appeared during or after an acute 
coronavirus infection (COVID-19) and persisting 4 to 12 weeks from the onset of coronavirus 
infection. 
After the patient signs the patient information sheet and the informed consent form for 
participation in the study, complaints, medical history, physical examination, registration of vital 
signs are collected, the patient fills in the Fatigue Severity Scale (FSS) and Hospital Anxiety and 
Depression Scale (HADS). A six-minute walk test (6MWT) is carried out. The physician evaluates 
the severity of asthenia with FSS scale and records concomitant medications, co-morbidities and 
concurrent conditions. 
If a patient meets all inclusion criteria and does not have any of the exclusion criteria at Visit 1 
(Day 1), he/she is randomized to one of two groups: Group 1 - patients receive Prospekta at a dose 
of 1 tablet twice daily for 4 weeks; Group 2 - patients receive placebo on the study drug regimen. 
The trial will use electronic patient diaries (EPD). The patient should record any possible 
deterioration (if applicable) in the EPD. At Visit 1 (Day 1), the physician will provide guidance 
on how to work with EPD, so that the patient can use it independently in the future. 
At Visit 2 (Week 4 ± 3 days), the physician will collect patient’s complaints, record physical 
examination data and vital signs as well as any changes in concurrent diseases and conditions. The 
patient fills out the FSS and HADS scales. A 6MWT is carried out. The physician monitors the 
prescribed treatment and use of concomitant medications, evaluates the safety of the study 
treatment and patient's compliance, filling out the diary.  
The patient stops taking the study drug. At the end of the study treatment period, the patient is 
monitored for 4 weeks (follow-up period). 
At Visit 3 (final visit, Week 8 ± 3 days), the physician collects patient’s complaints, records 
physical examination data and vital signs, changes in concomitant diseases and conditions. The 
patient fills in the FSS and HADS scales. A 6MWT is carried out. The physician evaluates the 
safety of the study treatment, checks the completion of the diary. 


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During the study the patients are allowed to take medications for their chronic conditions, except 
for medicines listed as "Prohibited concomitant treatment". 
Inclusion and exclusion criteria 
Inclusion criteria 
1. Adults of either gender aged 18 to 65 years inclusive. 
2. Patients within 4–12 weeks of the confirmed COVID-19 onset.  
3. Symptoms of asthenia that appeared during or after an acute new coronavirus infection 
(COVID-19), persisting from 4 to 12 weeks from the onset of coronavirus infection. 
4. Presence of asthenia (≥36 on the FSS scale).  
5. Patients who agreed to use a reliable method of contraception during the study (for men and 
women with reproductive potential). 
6. Presence of a signed information sheet and informed consent form for participation in the 
clinical trial. 
Exclusion criteria 
1.   History / suspicion of cancer of any localization (with the exception of benign neoplasms). 
2.   More than 75% of lung tissue damage during the period of COVID-19 disease (CT 4). 
3.   Cerebrovascular diseases with the development of moderate to severe cognitive impairments.  
4. Uncontrolled arterial hypertension characterized by the following blood tension values:   systolic 
blood pressure > 180 mm Hg and/or diastolic blood pressure > 110 mm Hg. 
5.   Myocardial infarction, stroke in the previous 6 months. 
6.   Nervous system disorders with persistent neurological impairment. 
7.   Autoimmune diseases. 
8.   Decompensated diseases of the cardiovascular system, liver, kidney, gastrointestinal tract, and 
metabolic, respiratory, endocrine or hematological diseases, peripheral vascular disorders. 
9.  Any severe comorbidity, which, in the opinion of the investigator, may affect patient 
participation in the clinical trial. 
10.  Hypersensitivity to any of the components of the study drug. 
11. Hereditary lactose intolerance, lactose malabsorption, including congenital or acquired lactase 
or other disaccharidase deficiency, galactosemia. 
12. Pregnancy, breast-feeding; childbirth less than 3 months prior to the inclusion in the trial, 
unwillingness to use contraceptive methods during the trial (for men and women with 
reproductive potential). 
13. Patients, who, from the investigator's point of view, will not comply with study observation 
requirements or study drug administration procedures. 


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14. Prior history of mental illness, alcoholism or drug abuse that the investigator's opinion will 
interfere with successful study procedures. 
15. Use of any medications listed in "Prohibited concomitant treatment" within 1 week before 
enrollment. 
16. Participation in other clinical studies within 3 months prior to enrollment in the study. 
17. Patients who are related to any of the on-site research personnel directly involved in the 
conduct of the trial or are an immediate relative of the study investigator. "Immediate relative" 
means husband, wife, parent, son, daughter, brother, or sister (regardless of whether they are 
natural or adopted). 
18. Participants who work for OOO "NPF "MATERIA MEDICA HOLDING" (i.e. the company's 
employees, temporary contract workers, designated officials responsible for carrying out the 
research or any immediate relatives of the aforementioned). 
Criteria for Withdrawal or Termination 
1. Screening failure.  
2. Inability or patient’s refusal to comply with the protocol requirements. 
3. Necessity in medications prohibited within the study. 
4. An adverse event requiring discontinuation of the study product. 
5. Patient’s decision to complete the study ahead of schedule due to lack of the therapy efficacy 
or any reasons. 
6. Pregnancy. 
7. Cases not specified by the protocol when, according to the investigator’s opinion, further 
participation in the study harms the patient.   
8. Eligibility error. 
9. Enrollment of the subject into another clinical study. 
10. Unblinding. 
Number of subjects 
It is expected that 272 trial subjects will sign the informed consent.   
At least 260 of the participants will be randomized. 
 


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Interim analysis 
A non-blind interim analysis will be carried out after 62 PP subjects complete the trial. Based on 
the results, the sample size may be increased up to 680 subjects (with the maximum number of 
randomized subjects being n=646). 
Treatment 
Group 1 
Name of the medicinal product: Prospekta 
Active ingredient: brain-specific protein S-100, modified – 10 000 UMA* 
* UMA – Units of Modifying Activity 
Excipients: Lactose monohydrate - 0.267g  
 Microcrystalline cellulose - 0.030 g  
                    Magnesium stearate - 0.003 g  
Method of administration: Per os. One tablet per intake 2 times a day (approximately at the same 
time), outside of meal (between meals or 15 minutes prior to meal or drinking). The tablet should 
be held in mouth until completely dissolved. The duration of therapy is 4 weeks. 
Dosage form: Tablets. 
Description: Flat cylinder-shaped scored beveled edge white to off-white tablets with smooth 
even surface. 
Storage conditions: At temperature ≤ 25 ºС. 
Group 2 
Name of the medicinal product: Placebo 
Active ingredient: No 
Excipients: Lactose monohydrate - 0.267 g  
                    Microcrystalline cellulose - 0.030 g  
                    Magnesium stearate - 0.003 g  
Method of administration: Per os. One tablet per intake 2 times a day (approximately at the same 
time), outside of meal (between meals or 15 minutes prior to meal or drinking). The tablet should 
be held in mouth until completely dissolved. The duration of therapy is 4 weeks. 
Dosage form: Tablets. 
Description: Flat cylinder-shaped scored beveled edge white to off-white tablets with smooth 
even surface. 
Storage conditions: At temperature ≤ 25 ºС. 
Treatment duration 
Prospekta/Placebo treatment duration is 4 weeks.  


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Observation period 
The total length of patient observation is 8 weeks (screening + randomization ‒ up to 1 day, 
treatment –4 weeks, follow-up ‒ 4 weeks).  
Symptomatic (Standard) treatment  
During the course of the study, the patient may receive therapy for concomitant diseases and 
conditions, with the exception of drugs listed in the "Prohibited Concomitant Treatment" section.  
Prohibited concomitant therapy 
Within 1 week prior to enrollment and during the study (beginning from signing patient 
information sheet and informed consent form) subjects are forbidden to take any therapy that can 
affect the psychoemotional and psychophysical status of the patient, the processes of excitation-
inhibition in the central nervous system (parenthesized is the ATC group): 
1.  Antiepileptic drugs (ATC group – N03A) 
2. Muscle relaxants (M03) 
3. Anticholinergic agents (N04A) 
4. Dopaminergic agents (N04В) 
5. Actovegin (В06) 
6. Psycholeptics (N05), including anxiolytics (tranquilizers), hypnotics and sedatives 
7. Psychoanaleptics (N06), including antidepressants, psychostimulants and nootropics 
including: 
• pyrrolidine derivatives (racetams) – piracetam, etiracetam, aniracetam, etc. 
• dimethylaminoethanol derivatives (acetylcholine precursors) - deanol aceglumate, 
meclofenoxate 
• pyridoxine derivatives - pyritinol, biotredin 
• GABA derivatives and analogues – gamma-aminobutyric acid, nicotinoyl gamma-
aminobutyric acid, gamma-amino-beta-phenylbutyric acid hydrochloride, hopantenic acid, 
calcium gamma-hydroxybutirate 
• gingko biloba 
• neuropeptides and their analogues - methionyl-glutamyl-histidyl-phenylalanyl-propyl-
glycyl-proline 
• amino acids and substances affecting excitatory amino acid system – glycine, 
pyrodoxine+threonine 
• 2-mercantobenzimidazole derivatives – ethylthiobenzymidazole hydrobromide 
• idebenon 
• vinpocetine 


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• polypeptides and organic composites - bovine cortical polypeptides, cerebrolysin 
• memantine (N06DX01) 
8. Glucocorticoids of systemic action (except for topical steroids) 
 
9. Tonics (A13) 
 
10. Anabolic agents for systemic use (A14) 
 
11. Other nervous system drugs (N07) including: 
•    parasympathomimetics (N07A) 
•    other nervous system drugs (N07X) 
12. Substances of other pharmacological group with a nootropic ingredient including: 
•    tonics and adaptogens – redberry, melatonin, lecithin, acetylaminosuccinic acid etc. 
•    antihypoxants and antioxidants – ethylmethylhydroxypyridine succinate, citicoline, 
vitamin E, etc. 
•    metabolic agents. 
13. Homeopathic preparations for the treatment of nervous system disorders 
14. Any unregistered product and/or vaccine 
12.   Drugs that previously caused allergic reactions in patient. 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prospekta 1 tablet twice a day for 4 weeks 
 
SCREENING 
RANDOMIZATION 
Visit 1 
(Screening, 
randomization 
Day 1) 
Placebo 1 tablet twice a day for 4 weeks 
Visit 2  
(Week 4±3 
days) 
 
8 weeks 
Visit 3  
(Week 8±3 
days) 
 
STUDY  
COMPLETION 
 
 
 
FOLLOW-UP 
 


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Schedule of study procedures  
 
Procedure/Visit 
Visit 1 
Screening, 
Randomization 
(Day 1) 
Visit 2 
(Week 4±3 days) 
Visit 3 
(Week 8±3 days) 
Informed consent 
+ 
 
 
Registration patient in IVWRS 
and assignment of a personal 
code 
+ 
 
 
Demographics 
+ 
 
 
Collection of complaints 
+ 
+ 
+ 
Medical history 
+ 
 
 
Concomitant conditions and 
diseases 
+ 
+ 
+ 
Physical examination 
+ 
+ 
+ 
Vital signs (HR, RR, BP)  
+ 
+ 
+ 
Registration of therapy for 
concomitant diseases 
+ 
+ 
+ 
Filling FSS scale 
+ 
+ 
+ 
Six Minute Walk Test 
+ 
+ 
+ 
Filling HADS scale 
+ 
+ 
+ 
Pregnancy test 
+ 
 
 
Inclusion/exclusion criteria 
+ 
 
 
Randomization 
+ 
 
 
Study drug supply 
+ 
 
 
Study drug accountability and 
return 
 
+ 
 
Compliance assessment 
 
+ 
 
Evaluation of treatment safety 
+ 
+ 
+ 
Visit completion 
+ 
+ 
+ 
Study completion 
 
 
+ 
 
Statistical Analysis 
Samples  
Total set includes all the subjects who have signed informed consent form (ICF). This sample will 
consider all adverse events (AEs) throughout the study, including those occurred prior to the study 
therapy.  
The sample including all subjects who received at least one dose of the study drug to be used for 
analysis of the study treatment safety and tolerability (Safety population), as all AEs identified 
after the study product administration will be registered.  


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Full Analysis Set. This sample will consist of all enrolled subjects, except for those who met at 
least one of the following criteria:  
1) non-compliance with inclusion/exclusion criteria;  
2) subject failing to take any dose of the study drug; 
3) lack of any data on the subject after the study drug administration.  
Patients who had at least one of the listed events may be excluded from the analysis. 
This was the best set for the Intention-to-treat method, so it will be used in the Intention-to-treat 
efficacy analysis (ITT-analysis) of the test therapy. 
Per Protocol set. This set will comprise all the subjects receiving per protocol therapy in full and 
completing all the scheduled visits. This set will be used for efficacy Per Protocol analysis (PP-
analysis). Per Protocol set will not include the subjects whose data are fully or partially invalid 
for analysis due to a protocol deviation. 
 Protocol deviations resulting in full or partial data invalidity: 
1. Violation of visit schedule. 
2. Inappropriate distribution/dispensing of the study drug. 
3. Prescription of prohibited therapy. 
4. Increase or decrease by 25% or more in the amount of study therapy taken. 
5. Inability to assess the subject's compliance using the formula (e.g. loss of pack with the 
product). 
6. Major discrepancies between source documents and CRF detected during monitoring or 
another authorized check.  
7. Violations of the informed consent procedure. 
8. Non-compliance with the clinical study protocol procedures. 
9. Inability to collect all subject's data used for evaluation of the study endpoints (e.g. lack of 
entries in source documents required for verification of inclusion/exclusion criteria, safety 
and efficacy criteria). 
10. Any other deviation from the protocol that falls under the definition of «major deviation».  
Data treatment and all statistical calculations under the protocol will be made using SAS-9.4 
statistical software.1 
Interim Analysis 
A “non-blinded” interim analysis is planned in the protocol for 25% of the sample (0.25 
information, for 31 subjects of the CT PP per group). 
                                                 
1 Holder of license: ООО "NPF "Materia Medica Holding", No. 70100045. 


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It is assumed that the study can be stopped due to the rejection of the null hypothesis with the 
O'Brien-Fleming type I error spending function. Based on the results of this analysis (if the stop 
parameters are not reached), it is assumed that the study will be adapted to determine the required 
additional sample size. The additional sample size will be determined according to the following 
algorithm2: 
1) The conditional power is calculated in the interim analysis; 
2) Depending on the value obtained, one of the three options for further research described below 
will be selected. 
At the discretion of the sponsor, a blind interim analysis may be performed to refine the population 
parameters and possibly further refine the sample size (upward only). 
Evaluation of sample size 
The sample size was assessed in accordance with the following rules and assumptions: 
1. Statistical assumptions 
1.1 the power of statistical tests «P = (1 − β)» is 80% (the probability of correct rejection of 
the null hypothesis is 0.8) 
1.2 the probability of type 1 error «α» is less that 5% (the probability of false acceptance of 
the alternative hypothesis is less than 0.05); 
1.3 the statistical criteria used for intergroup comparisons are two-sided unless otherwise 
noted;  
1.4 ratio between sample sizes of Prospekta and Placebo sample sizes is 1:1 (1 Prospekta 
subject per 1 Placebo subject); 
1.5 it is assumed to conduct a «non-blinded» interim analysis with the possibility of early 
termination due to the efficiency of 25% of the sample. Error spending function - O'Brien-
Fleming boundary; 
1.6 it is assumed that the sample size can be adapted after the interim analysis based on the 
estimated conditional power (simultaneously with the interim analysis); 
1.7 statistical hypotheses - null and alternative hypotheses on the difference between 
investigational product and placebo under the dosing regimen used: 
Primary Criteria: 
                                                   H0: M1- M2 = 0 
                                                   Ha: M1- M2 ≠ 0 
                                                 
2 Mehta, C.R. and Pocock, S.J. (2011), Adaptive increase in sample size when interim results are promising: A 
practical guide with examples. Statist. Med., 30: 3267-3284. https://doi.org/10.1002/sim.4102. 


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where M1 and M2 are values of change in the mean score of the questionnaire in the 
Placebo and Prospekta groups; 
The following SAS code was used to determine the required sample size3: 
executable SAS code (also defines critical statistics for the corresponding analyses) 
 Proc seqdesign errspend 
 Design nstages = 2 
 Info = cum (0.25,1) 
 Method (alpha) = UNI (rho = 0.5 tau = 0) 
 Method (beta) = UNI (rho = 0 tau = 0) 
 Stop = reject 
 Alpha = 0.05 
 Beta = 0.2 
 Samplesize model = twosamplemeans (meandiff = 0.65 stddev = 1.81) 
Run. 
1.8 the full sample size is determined by the formula: 
                                                        N=Npp/(1-Кв) 
where N – terminal sample size; NPP – sample size in c. 1.7 i.e. scheduled number of 
subjects completing the study per protocol; Кв – withdrawal rate. 
2. Assumptions on expected clinical study effects: 
It is assumed that there is an inter-group difference between the changes in the mean score 
of the FSS 0.654 questionnaire in favor of the Prospekta (the adaptation process assumes a 
possible deterioration in the effect prediction size to 0.41).                                              
Population standard deviation of change: assumed to be 1.815. Thus, for the first stage 
(before adaptation), the size of each of the groups of 1226 clinical study subjects is required (PP 
sample).  Considering the possible elimination of about 10% of the subjects in the study for 
various reasons7, at least 272 subjects will be required to sign informed consent, of which 260 
subjects of clinical trial will be randomized (130 subjects of clinical trials to each group) (see 
item 1.8, the final complete elimination rate will be Кв. = 0.1). 
                                                 
3 Minimum size for this study 
4 The change in the average FSS score was indicated during the study, for the calculation of which the sum of points on nine points is divided by 
9 (the average score lies in the range [1; 7]). 
5 Conservative assessment of the standard deviation: upper limit of 95% of the confidence interval of the standard deviation of the change in the 
mean score of the 9x questionnaire [1; 7] (measurements are considered independent, answers to individual questions are evenly distributed, the 
number of degrees of freedom for the distribution of the standard deviation of the average score is 8). 
6 Minimum size. 
7 Of these, the dropout of patients in the screening process (5%). 


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Sample size adaptation 
It is planned to adapt the sample size during the study according to the following algorithm8: 
1) During the planned interim analysis (if the study was not completed due to the rejection of 
the null hypothesis based on the interim analysis boundary), the conditional power is 
calculated  by the formula: 
 
where Z1 – value of Z-statistic obtained from interim analysis on N1 of the first participants   
from Nmin (minimum study sample size); 
Zα = 1.9603 (the value of statistics for the final analysis, taking into account the presence of 
an interim analysis); 
Φ(x) – probability value of event X for standard normal distribution (σ=1, μ=0). 
2) Maximum allowable increase in sample size to no more than 612 is assumed9. 
3)  Assumed minimum sample size Nmin = 260. 
4)  Based on the above, one of the adaptation scenarios will be selected. 
5) Optimistic scenario (conditional power CPower > 0.8, or equivalently Z1 > 1.3545): the 
sample size does not change (Nfinal = Nmin). 
6)  Mid-range scenario (conditional power 0.397 < CPower < 0.8, or equivalently 0.8744 < 
Z1 < 1.3545): the sample size changes according to the formula: 
 
7)  Pessimistic scenario (conditional power CPower < 0.3975, or equivalently Z1 < 0.8744): 
sample size does not change (Nfinal = Nmin). 
8)  The final statistical analysis is carried out with the critical values obtained during the 
assessment of the minimum sample size (Zα= 1.9603). 
 
Statistical criteria  
All statistical calculations will be made using two groups of statistical criteria:  
• 
parametric - to obtain effective estimates for random parameters in case the relevant 
conditions of method/model applicability are not violated (e.g. sphericity, normality, risk 
proportionality, etc.)  
• 
nonparametric – in all other cases. 
                                                 
8 Adaptive Increase in Sample Size when Interim Results are Promising: A Practical Guide with Examples. Cyrus R. Mehta1,2, Stuart J. Pocock3. 
Statistics in Medicine 2000; 00:1–6. 
9 Taking into account the elimination - up to 680. 


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Parametric criteria 
The application of parametric criteria will be accompanied by a check of models for applicability 
(e.g. Kolmogorov-Smirnov test, Shapiro-Wilk test). 
The following parameters and approaches are to be used: 
1. To evaluate the differences in continuous variables obtained in one group at two different 
visits – Student’s test for matched samples. 
2. To evaluate the time changes of the compared indicators - variance (ANOVA) or covariance 
(ANCOVA) analysis in modification with repeated measures (Repeated Measures).  
3. In case of multiple comparisons of the groups various corrections for multiplicity will be used, 
e.g. Dunnett, Tukey, Scheffe, Holm adapted test, etc.  
4. Generalized Linear Models and/or Mixed Linear Models will be used in case of abnormal data 
distribution.  
5. Selection of the type of distribution, specification of factor and covariance structures of the 
model will be made using fit-statistics such as AIC (Akaike information criterion). 
The following SAS software programs are supposed to be applied to the above listed tests and 
techniques:  
• UNIVARIATE – normality verification of the distributions under comparison 
• CORR, MEANS – calculation of descriptive statistics 
• TTEST – Student’s test with all modifications 
• GLM – generalized linear models for analysis of time changes (ANOVA, ANCOVA) 
• GENMOD – generalized linear models 
• MIXED – mixed linear models. 
Non-parametric criteria 
Below are potential types of comparisons with relevant criteria: 
1. To evaluate time changes in the parameters compared – Friedman test, nonparametric 
analogue of repeated measures analysis of variance. 
2. For frequency analysis of contingency tables 2×2 – χ2 (if the frequency under comparison > 
5) or exact Fisher’s test (if one of the frequencies under comparison < 5).  
3. Cochran-Mantel-Haenszel test (modified χ2 test for multiple comparisons) – to perform 
frequency analysis based on independent strata.  
4. For frequency analysis of data on presence/absence of an event or outcome during repeated 
measurements (contingency tables with dependent strata) – survival analysis.  
To perform the above-mentioned nonparametric statistical analysis the following SAS procedures 
are to be used:  
• FREQ – Friedman test, χ2 test and/or exact Fisher’s test; Cochran-Mantel-Haenszel test 


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• LIFETEST, PHREG – survival analysis 
• NPAR1WAY - Mann-Whitney U-test 
Safety parameters  
Adverse events recorded during the study will be grouped into frequency tables by severity, 
seriousness and relationship with the study drug.  
Data presentation 
Descriptive statistics will be provided for each study continuous / interval variable. Numerical data 
will be presented by mean, standard deviation, as well as maximum and minimum values, as well 
as 1, 2 and 3 quartiles (if necessary, other measures of central tendency and spread can be 
additionally given). The categorical variables will be presented as frequency tables by visits. 
Outliers will be analyzed individually. The data will be grouped by visits.