Comparative Effects of Moxonidine and Bisoprolol on Bone Metabolism, Vascular and Cellular Markers of Aging, Blood Pressure in Hypertensive Postmenopausal Women (COMPASS)
Phase: NA
Conditions: Osteopenia, Arterial Hypertension
Sponsor: National Research Center for Preventive Medicine



Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
CLINICAL TRIAL PROTOCOL 
 
1. 
STUDY TITLE:  
COMPARATIVE EFFECTS OF MOXONIDINE AND BISOPROLOL ON BONE 
METABOLISM, VASCULAR AND CELLULAR MARKERS OF AGING, BLOOD 
PRESSURE IN HYPERTENSIVE POSTMENOPAUSAL WOMEN (COMPASS) 
  
Protocol No.  
MOXOC001 
Version 
Version 1.0 
Date of the protocol final version: 
Study Sponsor: 
19/11/2014 
Autonomous Nonprofit Organization "Society of 
experts in innovative technologies in medicine" (ANO “OSO 
ITEM”) 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document contains confidential information not be 
disclosed except as required by law. Any person who became familiar with this document should 
be informed that he/she may not disclose the information. These restrictions on the information 
disclosure equally apply to any information that relates to the confidential data. 
 
 
1 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
PROJECT SYNOPSIS 
Study Title  
Comparative effects of moxonidine and bisoprolol on bone 
metabolism, vascular and cellular markers of aging, blood pressure in 
hypertensive postmenopausal women  
Study Sponsor: 
Autonomous Nonprofit Organization "Society of experts in innovative 
technologies in medicine" (ANO “OSO ITEM”) 
Principal 
Investigator  
O.N. Tkacheva, MD, PhD, professor 
Therapeutic area / 
indication 
Cardiology, essential hypertension 
Study objectives and 
goals  
Primary Objective: 
To investigate the effect of moxonidine versus bisoprolol on collagen 
type 1 C-telopeptide in postmenopausal female patients with arterial 
hypertension and osteopenia. 
Secondary Objectives:  
1. 
To investigate the effect of moxonidine versus bisoprolol on 
bone metabolism and bone tissue density in postmenopausal female 
patients with essential hypertension and osteopenia. 
2. 
To investigate the effect of moxonidine versus bisoprolol on the 
processes of cellular and vascular aging in postmenopausal female 
patients with essential hypertension and osteopenia. 
3. 
To investigate efficacy of antihypertensive therapy with 
moxonidine versus bisoprolol in hypertensive postmenopausal 
women.  
Study Design 
Randomized, open-label, interventional, comparative clinical trial  
Study 
population 
is 
postmenopausal 
women 
with 
essential 
hypertension and osteopenia. The study will enroll 114 patients after 
screening (it is expected that 300 patients will need to be screened to 
reach this enrolrollment goal). 
After the informed consent signing, the patient's participation in the 
study will include the period before the studied product 
administration, treatment period and a final visit. 
Patients will be randomized to one of two groups: moxonidine group 
or bisoprolol group. 
According to the study protocol, patients randomization to the control 
and investigated groups will be carried out using a simple envelopes 
method and, therefore, it is assumed that the control and the main 
groups will be matched by the basic measured parameters; the number 
of subjects in the main and control groups is planned to be equal. 
The study endpoints are measured prior to the studied product 
initiation (V1) and after completion of 48-week treatment with the 
investigated product (V4).  
2 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The period prior to the studied treatment initiation is designed to 
assess the patient meeting inclusion criteria and to carry out 7-10-day 
washout period in patients with previous antihypertensive therapy. 
The planned duration of the period before the treatment initiation does 
not exceed 14 days after the signing of the informed consent form by 
the patient. 
Then, at the enrollment visit during the treatment period, the 
investigator will assess the patient meeting the inclusion criteria. If the 
inclusion criteria are met, the patient will be enrolled in the study. The 
baseline condition data will be obtained from the patient, then the 
patient will be randomized to one of the two treatment groups 
(moxonidine or bisoprolol). The treatment period involves the 
enrollment visit (V1), and 3 more visits. 
The final visit 4 is carried out at week 48 after the enrollment visit, the 
patient then completes the study.  
The patients’ treatment includes gradual titration of the studied 
products doses.  
Group 1 will receive moxonidine with the dose titrated to a maximum, 
and then, if necessary, the patient will be shifted to the combination 
therapy (Step 2 – adding an ACE inhibitor) 
Group 2 will receive bisoprolol with the dose titrated to a maximum, 
and then, if necessary, the patient will be shifted to the combination 
therapy (Step 2 – adding an ACE inhibitor). 
After randomization to moxonidine and bisoprolol groups (V1), 
patients start treatment with 0.4 mg moxonidine QD or 5 mg 
bisoprolol QD. If the target BP (<140/90 mmHg) is reached in 2 
weeks, the patient continues taking the medication at the same dose. If 
the target BP is not reached in 2 weeks, the moxonidine dose is 
increased to 0.6 mg QD, the dose of bisoprolol is increased to 7.5 mg 
QD. If the target BP is not reached in 2 weeks of treatment with the 
increased doses, an ACE inhibitor (perindopril) at a dose of 10 mg/day 
is added at the 8th week of the study.  In case of intolerance to 
perindopril, losartan at a dose of 50 mg/day will be administered. 
During the study, the patient will have parameters of efficacy, 
tolerability and safety of the therapy with moxonidine or bisoprolol 
regularly assessed.  
Study Groups 
Investigated 
group: 
postmenopausal 
women 
with 
essential 
hypertension and osteopenia treated with moxonidine. 
Comparative 
group: 
postmenopausal 
women 
with 
essential 
hypertension and osteopenia treated with bisoprolol. 
Randomization 
procedure 
Simple randomization using the method of envelopes 
Number or patients 
114 patients. 
Screening inclusion 
criteria  
1. 
Female with age 45 years and older. 
2. 
Postmenopausal (absence of menstrual periods for a minimum 
of 12 months) at the moment of Informed Consent sign. 
3. 
Arterial hypertension grade I / II per ESH/ESC 2013 
3 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
JXLGHOLQHVGLDVWROLFSUHVVXUHDQG10 mm Hg, systolic pressure  
DQG80 mm Hg). 
4. 
Not achieving BP targets <140/90 mmHg either during 
antihypertensive therapy or naive.  
5. 
Absence of moxonidine or bisoprolol treatment at least 6 
months before the study 
6. 
Osteopenia of lumbar spine and/or proximal part of the femur 
(osteoporosis T-score from -1 to -2.5 standard deviations [SD]) by X-
Ray densitometry. 
7. 
Signed Informed Consent for participation in the study. 
Screening exclusion 
criteria  
1. Hypersensitivity to moxonidine, bisoprolol or any other 
ingredient of the respective formulations 
2. Any Contraindications for moxonidine, bisoprolol  
3. 2VWHRSRURVLVɌ-score below - 2.5 SD). 
4. Primary or secondary hyperparathyroidism. 
5. Paget’s disease of bones. 
6. History of low traumatic bone fractures. 
7. Malabsorption syndrome. 
8. History of gastro-intestinal surgery. 
9. Severe disturbance of peripheral circulation.  
10. Raynaud’s disease. 
11. Symptomatic (secondary) hypertension (caused by any 
primary internal diseases)  
12. Morbid obesity (BMI over 40 kg/m2). 
13. Symptoms of estrogen deficiency such as hot flushes, 
nights sweat, vaginal dryness 
14. Administration of any hormone-replacement therapy 
(HRT) or  intake of isoflavones 
15. Secondary hypogonadism. 
16. 6LVW%38PP+JDQGRU'LDVW%310 mm Hg. 
17. Clinical presentations of cardiovascular disease: coronary 
heart disease (CHD), history of stroke, transient ischemic 
attack (TIA), Charcot’s syndrome. 
18. Severe heart failure.  
19. Hemodynamically significant congenital heart disease. 
20. Heart rhythm disorders which require permanent use of 
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PHGLFDWLRQV
LQFOXGLQJ
ȕ-
adrenoblockers and calcium antagonists). 
21. Diabetes mellitus of any genesis. 
22. Severe liver failure. 
23. Severe kidney failure including patients on dialysis 
24. Thyroid diseases accompanied by functional disorders 
(thyrotoxicosis or uncompensated hypothyroidism).  
25. Alcohol and drug abuse. 
26. Patients with oncological diseases diagnosed within 5 
years before IC execution. 
27. Inability of the patient to comprehend the essence of the 
program and to provide his/her consent for participation 
4 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
in the program. 
28.  Patients with any condition, which in the opinion of the 
Investigator makes the patient unsuitable for inclusion 
based on clinical judgment. 
29. Corticosteroid therapy 
30. Participation in any other clinical study during the whole 
course of this investigation including participation in a 
study within 30 days prior to providing the informed 
consent for this trial 
 
Start of treatment 
criteria  
1) Patient is to meet all the inclusion criteria and should lack any of 
the exclusion criteria. 
2) Patients previously treated with antihypertensive agents have 
undergone 7-10-day washout period according to the protocol (all 
antihypertensive drugs are discontinued, except fast-acting agents to 
relieve hypertensive episodes). 
Duration of the study 
Patients’ enrollment – 12 months.  
The total duration of the study is 48-50 weeks.  (Screening period (1-
14 days) and washout period (7-10 days), every patient will be treated 
for up to 48 weeks).  
 
FPFV – Q1.2015 
LPFV – Q1.2016 
LPLV – Q1.2017 
CSR   – Q3.2017 
Investigated product.  
Dose, method of 
administration 
Film-coated tablets of Moxonidine (Physiotens) manufactured by 
Rottendorf Pharma GmbH, Germany, packaged and released by 
Abbott Healthcare SAS, France. 
One tablet contains 0.40 mg moxonidine as an active substance and 
the following excipients: lactose monohydrate - 95.60 mg; povidone 
K25 - 0.70 mg; crospovidone – 3.00 mg; magnesium stearate - 0.30 
mg; hypromellose 6mPas - 1.300 mg; ethyl cellulose aqueous 
Disp.30% - 4.000 mg (solids 1.200 mg) ; macrogol 6000 - 0.250 mg; 
talc - 0.875 mg; red ferric oxide (E172) - 0.125 mg; titanium dioxide 
(E171) - 1.250 mg. There are 14 tablets in the blister; the carton 
contains 1, 2 or 7 blisters. 
One tablet contains 0.20 mg moxonidine as an active substance and 
the following excipients: lactose monohydrate - 95.80 mg; povidone 
K25 - 0.70 mg; crospovidone – 3.00 mg; magnesium stearate - 0.30 
mg; hypromellose 6mPas - 1.300 mg; ethyl cellulose aqueous 
Disp.30%- 4.000 mg (solids 1.200 mg); macrogol 6000 - 0.250 mg; 
talc - 0.9975 mg;  red ferric oxide (E172) - 0.0025 mg; titanium 
dioxide (E171) - 1.250 mg. There are 14 tablets in the blister; the 
carton contains 1, 2 or 7 blisters. 
 
5 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Moxonidine is taken orally, once or twice a day, regardless of meals. 
Maximum daily dose of moxonidine is 0.6 mg. 
 Duration of treatment: Moxonidine 0.4 mg is prescribed to 
postmenopausal patients with hypertension and osteopenia once or 
twice a day. Subsequently, in patients with no response, the daily dose 
is titrated up to 0.6 mg QD; then perindopril 10 mg may be added to 
the regimen at week 8, if necessary. In case of intolerance to 
perindopril, losartan at a dose of 50 mg/day will be administered. 
Comparative 
product. 
Dose, method of 
administration 
Bisoprolol, film-coated tablets 
One tablet contains bisoprolol hemifumarate and bisoprolol 
fumarate (2: 1) as active substances 5 mg, and the following 
excipients: calcium hydrogen phosphate anhydrous - 132 mg; corn 
starch fine powder - 14.5 mg; colloidal anhydrous silica - 1.5 mg; 
MCC - 10 mg; crospovidone - 5.5 mg; magnesium stearate - 1.5 mg 
  
  
 
  
film coating: hypromellose 2910/15 - 2.2 mg; macrogol 400 - 0.53 
mg; dimethicone 100 - 0.11 mg; iron oxide yellow dye (E172) - 
0.02 mg; titanium dioxide (E171) - 0.97 mg. 
Bisoprolol is taken orally, once a day, regardless of meals. 
Bisoprolol 5 mg is prescribed to postmenopausal patients with 
hypertension and osteopenia. Subsequently, in patients with no 
response, the daily dose is titrated up to 7.5 mg every 2 weeks; then 
perindopril 10 mg may be added to the regimen at week 8, if 
necessary. In case of intolerance to perindopril, losartan at a dose of 
50 mg/day will be administered. 
 
Other agents allowed 
by the protocol  
Losartan film-coated tablets produced by Berlin-Chemie, Germany.  
Each tablet contains 50 mg of losartan.  
Losartan is taken orally, once a day, regardless of meals. The product 
is prescribed to postmenopausal patients with hypertension and 
osteopenia non-responsive to moxonidine or bisoprolol monotherapy 
for 4 weeks and intolerant to perindopril. 
Calcium carbonate + cholecalciferol, chewable tablets 
Each tablet contains the following active ingredients calcium 
carbonate 1250 mg (equivalent to 500 mg of elemental calcium), 
cholecalciferol (vitamin DΎ) 5 mcg (200 IU) (as cholecalciferol 
concentrate - 2 mg).   
  
excipients: sorbitol - 390 mg; isomalt - 62 mg; povidone - 36.4 
mg; magnesium stearate - 6 mg; aspartame - 1 mg; orange oil - 
0.97 mg; mono- and diacylglycerols - 0.0008 mg. 
The product is taken orally during meals, it should be chewed or 
dissolve in the mouth. 
 
 
 
6 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Endpoints 
Primary endpoint: 
Changes in mean values of the bone resorption marker (collagen type 
1 C-telopeptide) at the end of the study (V4) from the baseline (V1) in 
comparison between the groups. 
Secondary endpoints:  
1) 
To assess mean values of osteocalcin at visit 4 versus baseline 
level (visit 1) and comparison between the groups   
2) 
To assess mean values of the receptor activator of nuclear 
factor kappa-B ligand (RANKL) at visit 4 versus baseline level (visit 
1) and comparison between the groups   
3) 
To assess mean values of BMD at visit 4 versus baseline level 
(visit 1) using control dual-energy X-ray absorptiometry and 
comparison between the groups   
4) 
To assess mean telomerase activity at visit 4 versus baseline 
level (visit 1) and comparison between the groups   
5) 
To assess mean pulse wave velocity (PWV) at visit 4 versus 
baseline level (visit 1) and comparison between the groups   
6) 
To assess mean intima-media thickness (IMT) at visit 4 versus 
baseline level (visit 1) and comparison between the groups   
7) 
To estimate the proportion (%) of patients who achieved target 
blood pressure <140/90 mmHg at the visit 2 (week 8), visit 3 (week 
24) and 4 (Week 48) and according to the patient's diary. 
Evaluation of 
pharmacokinetic / 
pharmacodynamic 
parameters  
The parameters will not be evaluated  
Evaluation of quality 
of life / 
pharmacoeconomic 
parameters  
The parameters will not be evaluated  
Statistical Analysis 
Efficacy Analysis: 
Changes in mean values of the bone resorption marker (collagen type 
1 C-telopeptide) at the end of the study (V4) from the baseline (V1) 
are evaluated in comparison between the groups. 
Changes in mean values of the receptor activator of nuclear factor 
kappa-B ligand (RANKL) at visit 4 versus baseline level (visit 1) in 
comparison between the groups. 
Changes in mean values of BMD at visit 4 versus baseline level (visit 
1) using control dual-energy X-ray absorptiometry and in comparison 
between the groups.   
7 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Changes in mean telomerase activity at visit 4 versus baseline level 
(visit 1 in comparison between the groups.   
Changes in mean pulse wave velocity (PWV) at visit 4 versus baseline 
level (visit 1) and in comparison between the groups. 
Changes in mean intima-media thickness (IMT) at visit 4 in 
comparison between the groups. 
The efficacy of the investigated treatment is estimated based on 
whether target blood pressure (<140/90 mm Hg) at visits V2, V3 and 
V4 is reached. 
Safety Analysis: 
Adverse events (AEs) are recorded at every visit. Analysis of adverse 
events and serious adverse events is conducted to determine the total 
number of AEs, the total number of patients with adverse events, the 
number of treatment-related adverse events, the number of AEs 
associated with product discontinuation and the number of voluntary 
withdrawal of informed consent. 
Rate and severity of all adverse events and drug-related adverse events 
(i.e., at least “possibly” associated with the studied product) will be 
summarized by organ systems. Data on the product withdrawal due to 
adverse events will be summarized in tables. 
 
Statistical methods: 
Statistical analysis will be conducted under the supervision of a 
responsible biostatistician. The details of statistical analysis will be 
provided in the statistical analysis plan in accordance with the GCP 
requirements and other relevant requirements and laws. The statistical 
analysis plan will be finalized before the data lock point. All 
deviations from the final statistical plan version will be justified in the 
final program report.  
The results will be combined for the complete study sample. Two-
sided levels of significance and confidence intervals will be 
calculated. The significance of differences will be calculated for two-
sided tests, with a critical significance level of 0.05.  
For parameters of interval scale type, the following will be calculated: 
the arithmetic mean (95% confidence interval for the mean), standard 
deviation, median, 25th and 75th percentiles. For parameters of 
ordinal scale type, median, 25th and 75th percentiles will be 
calculated. For parameters of nominal scale type, frequency categories 
and confidence intervals for the frequencies (modified Wald method) 
will be calculated. If the assumptions made during the preliminary 
study planning are found to be erroneous, the analysis methods will be 
modified to conduct a more suitable analysis.  The result of the 
primary endpoint analysis will be presented as an absolute number and 
8 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
proportion (%) of patients with target BP (<140/90 mm Hg) achieved 
at visit V4. 
Statistical analysis will be carried out using SPSS / PASW Statistics 
software package (version 18), SPSS Inc., Chicago, Illinois, USA. 
 
Rationale for sample size  
As this is an explorative study with open design no formal sample size 
calculation was performed. The focus of the study is to obtain 
scientific data for a publication and taking into account a reason of 
feasibility of enrollment to timelines and screening of 300 patients per 
year in assumption that ratio of screened / enrolled patients is 
approximately 3 to 1  so it is expected that not less than 100 patients 
but no more than 114 patients will be enrolled in the study. According 
to this approach the total sample size is chosen 114 subjects. 
 
 
9 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
ACEI - angiotensin-converting enzyme inhibitor  
AE - adverse event  
ALT - alanine aminotransferase 
AR - adverse reaction 
AST - aspartate aminotransferase 
BB - beta-blockers 
BMD - bone mass density 
BMD - bone mineral density 
BP - blood pressure 
CHD - coronary heart disease 
CRF - case report form 
CTX - collagen type 1 C-telopeptide   
CVD - cardiovascular disease 
DBP - diastolic blood pressure 
ECG - electrocardiogram 
HCF - health care facility 
HR - heart rate 
HTN - hypertension 
IMT - intima-media thickness  
OC - osteocalcin 
OPG - osteoprotegerin 
PWV - pulse wave velocity 
RANKL - Receptor activator of nuclear factor kappa-B ligand  
SAE - serious adverse event 
SBP - systolic blood pressure 
TIA - transient ischemic attack 
 
 
10 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Site conducting the study – Federal State-Funded Institution “State Scientific Research 
Center of Prophylactic Medicine” of the Ministry of Healthcare of Russian Federation (FSFI 
“SSRCPM” of the Ministry of Healthcare of Russia) 
Principal Investigator – O.N. Tkacheva, MD, PhD, professor 
1. INTRODUCTION 
1.1 Rationale 
 
It is known that cardiovascular disease (CVD) associated with atherosclerosis is the 
major cause of morbidity, disability and mortality in developed countries and, according to 
WHO estimates, in the next decade, CVD may become the leading cause of death in developing 
countries as well [1]. At the same time, the CVD epidemic is unfolding in the setting of 
significant advances in the diagnosis and treatment of these conditions.   One reason for such a 
dramatic increase in heart attack, stroke, and heart failure incidence is thought to be the steadily 
aging population. It is due to the fact that age-related changes of blood vessels are an important 
risk factor for CVD.  Growing evidence has been accumulated that aging-related changes in the 
vascular wall produce metabolically and enzymatically active environment that promotes 
initiation and progression of vascular disease. The more pronounced the age-related vascular 
wall changes are, the easier and faster atherosclerosis, hypertension and other CV disorders 
develop, which, in turn, accelerates the age-related changes.  
The main signs of vascular aging include arterial wall thickening, subclinical 
atherosclerosis, vascular calcification and increased arterial stiffness, of which the increased 
vascular stiffness is a key sign of vascular aging [2, 3].  It is known that aside from hypertension, 
the chronic indolent inflammation associated insulin resistance plays a fundamental role in the 
increase of vascular wall stiffness [4]. In recent years, more data have been accumulated on the 
role of cellular senescence in the development of vascular aging.  One of the major theories of 
cellular senescence is based on the telomere shortening.  A telomere is a region of repetitive 
nucleotide sequences (TTAGGG) at the end of a linear chromosomal DNA.  The main 
mechanism for maintaining telomere length is the restoration of telomere repetitive DNA 
sequences by the enzyme telomerase.  The assessment of telomerase enzyme activity in 
combination with other parameters enables to evaluate the rate of aging [5, 6]. Accelerated 
11 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
telomere shortening and reduced telomerase activity may be due to oxidative stress, chronic 
inflammation and their associated processes, e.g., insulin resistance [7, 8]. 
It is believed that vascular and cellular markers of aging may be a useful additional 
criterion for evaluation of long-term effectiveness of therapy for chronic non-infectious diseases, 
e.g., arterial hypertension.   
The postmenopause is a period in a woman’s life that is characterized by accelerated 
aging processes, higher risk of hypertension and progressive insulin resistance.   
 There is no doubt that the search for effective targeted therapy of the main chronic non-
infectious diseases aimed at not only treatment of the disease but also at slowing of the aging 
itself is a very promising research area.  
Earlier clinical trials revealed a positive effect of moxonidine on insulin resistance 
suggesting that the drug may be a promising antihypertensive agent with a potential effect on 
cellular and vascular aging [9].   
Other antihypertensive drugs have a short-term effect on the functional state of the 
arterial wall (owing to smooth muscle relaxation) and a long-term effect on its structure 
(primarily due to quantitative and qualitative changes in elastin and collagen).  A meta-analysis 
based on the results of 15 randomized clinical studies has demonstrated that the arterial stiffness 
may be reduced in patients administered with antihypertensive medications regardless of the 
intensity of the antihypertensive effect [10].   
Reduction of arterial stiffness in hypertensive patients was noted for ACE inhibitors, 
beta blockers (BB), angiotensin II receptor blockers, and calcium antagonists [11].  
Along with hypertension, osteoporosis is one of the most pressing problems of women's 
health.  Among all known forms of osteoporosis, the postmenopausal osteoporosis accounts for 
85% of all osteoporosis cases. As we age, the bone metabolism is shifted towards bone 
resorption that leads to osteopenia, and to osteoporosis in subjects predisposed to rapid loss of 
the bone mass [12].  Bone strength depends on the amount of bone mass and quality of the bone 
tissue. Bone mineral density (BMD) is the measure of bone mass, while the bone tissue quality is 
characterized by bone turnover that is evaluated with biochemical markers of bone formation 
(e.g., osteocalcin, OC) and bone resorption (e.g., collagen type 1 C-telopeptide, CTx).  
12 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Several experimental studies have demonstrated that moxonidine may lower the activity 
of Na+- independent Cl-/bicarbonate exchanger (anion exchanger, AE) which plays an essential 
role in viability of osteoclasts that are crucial for bone resorption. The suppression of AE 
proteins activity has been proven to inhibit osteoclast activity and reduce bone resorption 
whereas the moxonidine molecule is known to reduce the AE protein activity. Therefore, the 
results of experimental studies have shown the ability of moxonidine to inhibit bone resorption 
through its effect on the osteoclast activity. Furthermore, the experimental studies demonstrated 
the ability of moxonidine to slow down the loss of the bone mass in laboratory animals which 
lays a foundation for clinical investigation of moxonidine effects on bone tissue density [9].   
The discovery of the signaling system that includes receptor activator of nuclear factor 
ɤȕ 5$1. LWV OLJDnd (RANKL) and osteoprotegerin (OPG) acting as a main regulator of 
differentiation, functioning and apoptosis of osteoclasts, has made a breakthrough in the 
understanding of pathophysiology of osteoporosis. RANKL is produced by cells of osteoblast 
lineage, bone marrow stromal cells, synovial cells and activated T-cells. RANKL binds to OPG 
and plays the coordinating role in osteoclastogenesis, osteoclasts differentiation, activation and 
apoptosis.  RANKL activation is an important preliminary step in osteoclast production and 
occurs with RANKL binding to pre-osteoclasts. OPG is a natural decoy receptor for RANKL and 
competes with RANK for binding RANKL.  By blocking such binding, OPG suppresses bone 
resorption in favor of bone formation. The abnormal binding of RANKL to OPG is an essential 
link in the pathogenesis of many diseases associated with increased production of RANKL and 
increased bone resorption [13]. 
Vascular wall calcification is the most important aspect of the age-related changes. A 
number of studies have established that there is a clear inverse correlation between the degree of 
vessels calcification and the level of bone mineralization. This phenomenon was called the 
calcification paradox.  Once the key proteins that stimulate or inhibit the extraskeletal 
calcification have been discovered, it has become clear that the vascular calcification is not only 
a passive process of calcium and phosphorus deposition but also an active process that involves 
vascular “ossification”.  Numerous authors have confirmed the association between osteoporosis 
and vascular calcification in a general population [14].  
13 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Of all the components that most clearly indicate the link between bones and arterial 
wall, OPG attracts major attention. OPG is a part of a system whereby the osteoblasts modulate 
the osteoclastogenesis. 
Increased OPG levels have been found in postmenopausal women with osteoporosis 
versus healthy women of corresponding age.  It is suggested that the increased OPG level is a 
compensatory reaction to the increased osteoclast-mediated bone resorption. Normally, RANKL 
is not expressed in the vessels, however, its expression was found in OPG-deficient mice and in 
aortic valves of patients with calcified aortic valve stenosis.  The elevated RANKL may be a link 
between bone tissue and vascular calcification [15].   
All the above data suggest that the broadening of knowledge about OPG effects on the 
arterial wall and bones allows us to understand clinical and therapeutic value of OPG in 
osteoporosis and vascular calcification. 
Published data contain information on positive effects of beta-blockers on the bone 
tissue condition. There are data which clearly demonstrate a positive effect of beta-blockers on 
bone mass. Thus, Australian researchers in a large-scale 20-year-long study involving 3488 
patients have shown that a regular intake of beta blockers (BB) can increase bone mineral 
density (BMD) and prevent osteoporosis in 50% of patients [16]. 
In the population-based study of women older than 50 years (Geelong Osteoporosis 
Study), the association between beta blockers treatment and bone mineral density (BMD) or 
bone fractures has been estimated. The results have confirmed the association between the 
treatment with beta blockers and high level of BMD or low risk of bone fractures [16]. 
However, there are other studies that failed to confirm a positive effect on beta blockers 
on BMD (Study of Osteoporosis Fructures, Danish Osteoporosis Prevention Study, EPIDOS, 
Rotterdam Study). These studies pursued other goals and the effects of beta blockers on BMD 
were analyzed retrospectively. The analysis of the beta blockers efficacy was also complicated 
by the fact that the investigated group and the comparative group of patients differed from each 
other greatly in confounding factors that may have affected the amount and quality of the bone 
tissue (body mass, hormonal replacement therapy, smoking, statins and glucocorticoids 
treatment, etc.). Thus, there is currently no sufficient clinical experience to draw definitive 
conclusions about effects of beta blockers on BMD.   
14 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The proposed trial is a comprehensive study of moxonidine effects on processes of 
cellular and vascular aging as well as bone metabolism. We may not rule out a possible role of 
moxonidine in formation of calcification paradox. 
2. PROGRAM OBJECTIVES  
2.1 Primary objective:  To investigate the effect of moxonidine versus bisoprolol on 
collagen type 1 C-telopeptide in postmenopausal female patients with arterial hypertension and 
osteopenia. 
2.2 Secondary (experimental) objectives:  
To investigate the effect of moxonidine versus bisoprolol on bone metabolism and bone 
tissue density in postmenopausal female patients with essential hypertension and osteopenia. 
To investigate the effect of moxonidine versus bisoprolol on the processes of cellular 
and vascular aging in postmenopausal female patients with essential hypertension and 
osteopenia. 
To investigate efficacy of antihypertensive therapy with moxonidine versus bisoprolol 
in hypertensive postmenopausal women.  
 
3. PROGRAM PLAN AND PROCEDURES   
3.1 General design 
This is explorative, randomized, open-label, interventional, comparative clinical trial. 
Study population is postmenopausal women with essential hypertension and osteopenia. 
The study will enroll 114 patients after screening (it is expected that 300 patients will need to be 
screened in order to reach this enrollment goal). 
After the informed consent signing, the patient's participation in the study will include 
the period before the studied product administration, the treatment period and the final visit. 
Patients will be randomized to one of two groups: moxonidine group or bisoprolol 
group. 
According to the study protocol, patients randomization to the control and investigated 
groups will be carried out using a simple envelopes method and, therefore, it is assumed that the 
control and the investigated groups will be matched by the basic measured parameters; the 
number of subjects in the main and control groups is planned to be equal. 
The study endpoints are measured prior to the studied product initiation (V1) and after 
completion of 48-week treatment with the investigated product (V4).  
15 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The period prior to the studied treatment initiation is designed to assess the patient 
meeting inclusion criteria and to carry out 7-10-day washout period in patients with previous 
antihypertensive therapy. The planned duration of the period before the treatment initiation does 
not exceed 14 days after the signing of the informed consent form by the patient. 
Then, at the enrollment visit during the treatment period, the investigator will assess the 
patient meeting the inclusion criteria. If the inclusion criteria are met, the patient will be enrolled 
in the study. The baseline condition data will be obtained from the patient, and then the patient 
will be randomized to one of the two treatment groups (moxonidine or bisoprolol). The treatment 
period involves the enrollment visit (V1), and 3 more visits. 
The final visit 4 is carried out at week 48 after the enrollment visit, the patient then 
completes the study.  
The patients’ treatment includes gradual titration of the studied products doses.  
Group 1 will receive moxonidine with the dose titrated to a maximum, and then, if 
necessary, the patient will be shifted to the combination therapy (Step 2 – adding an ACE 
inhibitor) 
Group 2 will receive bisoprolol with the dose titrated to a maximum, and then, if 
necessary, the patient will be shifted to the combination therapy (Step 2 – adding an ACE 
inhibitor). 
After randomization to moxonidine and bisoprolol groups (V1), patients start treatment 
with 0.4 mg moxonidine QD or 5 mg bisoprolol QD. If the target BP (<140/90 mmHg) is 
reached in 2 weeks, the patient continues taking the medication at the same dose. If the target BP 
is not reached in 2 weeks, the moxonidine dose is increased to 0.6 mg QD, the dose of bisoprolol 
is increased to 7.5 mg QD. If the target BP is not reached in 2 weeks of treatment with the 
increased doses, an ACE inhibitor (perindopril) at a dose of 10 mg/day is added at the 8th week 
of the study.  In case of intolerance to perindopril, losartan at a dose of 50 mg/day will be 
administered. 
During the study, the patient will have parameters of efficacy, tolerability and safety of 
the therapy with moxonidine or bisoprolol regularly assessed. 
The study design is shown in Figure 1.  
 
16 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Figure 1. The overall study design 
Screening
Moxonidin
0,4 mg 
Moxonidin
0,6 mg 
Moxonidin 0,6 mg +
Perindopril 10 mg
Bisoprolol
5 mg
Bisoprolol
7,5 mg
Bisoprolol
ϳ͕ϱ̥̭̱̯̐ͬ +
Perindopril
ϱ̥̭̱̯̐ͬ
V 1
Day 0
TV2
TV1
V 2
W 8
V 4
W 48
V 3
W 24
Washout
period
Randomization
V 0
Day -14
 
3.2 Patients randomization and identification 
The study participants are randomized using a simple envelopes method. An 
independent person will generate a random table for 114 records in which 57 will be marked as 
“M” and 57 will be marked as “B”. According this computer based randomization table cards 
with letter “B” or “M” will be sealed in 114 numbered envelopes.  The randomization table will 
also be sealed in a separated envelope. The numbered envelopes will be sent to Principal 
Investigator.  The envelope with randomization table will be stored in the Sponsor file. 
Each patient is assigned with a special identification code that is only used in the 
program. The code is assigned to a patient after enrollment and includes the health care facility 
code and the patient number.  
According to the protocol, decoding keys for the identification codes are not provided. 
Persons authorized by the Sponsor, health care or other regulatory authorities may inspect any 
program data available to the investigator. 
3.3 Study duration  
The total duration of the study is 48-50 weeks.  
17 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Patients’ enrollment – 12 months. After screening period (1-14 days) and washout 
period (7-10 days), every patient will be treated for up to 48 weeks. 
3.4 Schedule of the study procedures 
Prior to the study enrollment, examination to assess conformity with the 
inclusion/exclusion criteria, to obtain baseline data and ensure washout period (if necessary) will 
be carried out for a patient. After enrollment and initiation of the investigated treatment, the 
study procedures will be conducted to assess product tolerability, safety, efficacy and patient 
compliance. All scheduled visits are mandatory. Washout period will be carried out only for 
patients with prior antihypertensive therapy. Each patient is to sign the informed consent prior to 
any study activities including screening / “examination to assess conformity with the in- and 
exclusion criteria. 
Schedule of the study procedures is presented in Table 2. 
 
Visit 0 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
 
Day-14…-1 
Day 0 
Week 8 
Week 24 
Week 48 
Drug administration 
 
+ 
+ 
+ 
+ 
Dose titration / treatment 
adjustment 
 
+ 
+ 
+ 
 
BP / HBR / Patients’ diary 
analysis 
+ 
+ 
+ 
+ 
+ 
ECG, K, Na 
+ 
 
 
+ 
 
Creatinine 
+ 
 
 
+ 
 
ALT/AST 
+ 
 
 
+ 
 
Parathyroid hormone 
+ 
 
 
 
 
X-ray densitometry, BMD 
+ 
 
 
 
+ 
Total calcium, Phosphorus 
+ 
 
 
+ 
+ 
PWV 
 
+ 
 
 
+ 
IMT + evaluation of subclinical 
atherosclerosis 
 
+ 
 
 
+ 
Telomerase activity 
 
+ 
 
 
+ 
Osteocalcin 
 
+ 
 
+ 
+ 
Collagen type 1 C-telopeptide 
 
+ 
 
+ 
+ 
Osteoprotegerin, RANKL 
 
+ 
 
 
+ 
Safety Information 
+ 
+ 
+ 
+ 
+ 
 
 
3.5 Number of patients:  
114 patients will be enrolled to the study to ensure the final sample size. The patients will be 
randomized to one of two treatment groups (moxonidine group or bisoprolol group) using simple 
18 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
randomization envelopes. It is anticipated that a screening of 300 subjects will be needed in 
order to enroll the minimum of 100 patients to the study. 
According to the study protocol, patients randomization to the control and investigated 
groups will be carried out randomly and, therefore, it is assumed that the control and the 
investigated groups will be matched by the basic measured parameters; the number of subjects in 
the main and control groups is planned to be equal. 
The study endpoints are measured prior to the studied product initiation (V1) and after 
completion of 48-week treatment with the investigated product (V4).  
3.6 Study procedures 
3.6.1 Screening and washout periods (V0) 
Any patient screening procedures are conducted only after the informed consent to 
participate in the study is signed. After the informed consent is signed, the patient is assigned 
with a screening number and the following procedures are performed. 
The investigator collects patient demographic data (gender, age), significant life history, 
detailed medical history (duration of hypertension, current antihypertensive drugs and duration 
of their use), and assesses hypertension severity and grade according to the ESH/ESC 
recommendations that are listed in Appendix 1. The investigator asks questions about the 
patient's history of cardiovascular disorders and other significant comorbidities and their 
treatment.  
The researcher gathers information about medications that patient’s used during 30 days 
prior to the screening, asks about intolerance to antihypertensive drugs, especially I1-imidazoline 
receptors, beta-blockers and ACE inhibitors. 
After the conversation with the patient, the investigator conducts a physical examination 
of organs and organ systems that must include measurement of heart rate, systolic and diastolic 
blood pressure according to ESH/ESC recommendations that are listed in Appendix 1 [17]. BP is 
first measured on the right and left arms. Thereafter, during the remaining study period, blood 
pressure should be measured at the arm with the highest blood pressure on screening. Resting 
heart rate (bpm) is measured by the standard method used in the physician routine practice. It is 
recommended to count heart rate for 60 seconds in a sitting position after 5 minutes of rest three 
times with 2-3 minutes interval between the measurements. 
19 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Blood pressure and heart rate are measured in a sitting position after 5 minutes of rest. 
Three measurements are carried out, the average value of the measurements is recorded.  
The patient will have the resting standard 12-lead ECG registered. The investigator will 
record all clinically significant ECG abnormalities. 
If the data obtained meet the screening criteria, biochemical (potassium, sodium, 
creatinine, total calcium, inorganic phosphorus, ALT, AST) and hormone (PTH) fasting blood 
tests will be conducted for the patient. 
Results of the tests (CBC, BMP, pregnancy test) should be obtained prior to the 
washout period initiation and patient enrollment to verify compliance with screening criteria.  
Dual energy X-ray absorptiometry to determine BMD and detect osteopenia will be 
performed.  
After screening investigation results are obtained, if the patient meets screening criteria, 
the investigator: 
x 
Schedules visit V1 for primary patients and patients who were only administered 
with fast acting antihypertensives to relieve a hypertension episode; 
x 
Starts washout period for patients taking antihypertensive drugs at the time of 
screening visit, before proceeding to visit V1. 
During the washout period, the investigator will ask the patient to refrain from taking 
her prior antihypertensives and other antihypertensives. The investigator may prescribe the 
patient with short acting antihypertensives to relieve a hypertension episode (at the investigator 
discretion: nifedipine, captopril or other acting products for urgent blood pressure lowering). 
Also, a modified lifestyle will be advised, e.g., dieting (according to ESH/ESC 
recommendations that are listed in Appendix 3), cessation of smoking, physical exercises. 
For washout period conditions and requirements please refer to “Treatment of 
patients”. 
If the patient does not meet the screening criteria, she should not proceed with the 
following visits and her data and reason for withdrawal from the study are recorded in the 
screened patients accountability form. 
3.6.2 Enrollment visit (V1) 
Enrollment visit is conducted no later than 14 days after signing the informed consent 
form by the patient. 
20 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The investigator documents all significant changes in the history of hypertension and 
concomitant treatment (including fast acting antihypertensives to relieve a hypertension episode 
that may be administered during the washout period); the investigator identifies and documents 
adverse events associated with the protocol procedures, if any, starting from the date of the 
informed consent signing.  
The investigator conducts a physical examination of the patient by organs and organ 
systems that must include measurement of heart rate, systolic and diastolic blood pressure 
according to ESH/ESC recommendations that are listed in Appendix 1 [17]. Blood pressure and 
heart rate are measured in a sitting position after 5 minutes of rest on the arm with the highest BP 
during screening.  Three measurements are done; the average value of the measurements is 
documented. The investigator assesses hypertension severity and grade according to the 
ESH/ESC recommendations that are listed in Appendix 2. 
Applanation tonometry method is used to measure changes in patient’s PWV; duplex 
ultrasonography of extracranial brachiocephalic arteries is employed to evaluate IMT and 
subclinical atherosclerosis. 
Blood is sampled to investigate bone metabolism: osteocalcin, Ctx, OPG, RANKL. 
Blood is sampled to determine telomerase activity. 
The investigator may enroll the patient in the study and start the investigated treatment 
only if the patient meets all the screening criteria to start the treatment. 
The investigator randomizes patients to one of two treatment groups by means of the 
simple envelopes method. 
 
Treatment regimens 
x 
Group 1 patients receive moxonidine with dose titration up to the maximum, then 
a patient may be switched to the combination therapy, if necessary (step 2 - adding an ACE 
inhibitor).  
x 
Group 2 patients receive bisoprolol with dose titration up to the maximum, then a 
patient may be switched to the combination therapy, if necessary (step 2 - adding an ACE 
inhibitor).  
21 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The investigator will provide a Group 1 patient with moxonidine 0.4 mg in the amount 
required for 56 days of treatment plus 7 extra days and additionally moxonidine 0.2 mg in an 
amount required for 42 days of treatment if the dose is titrated up to 0.6 mg/day. 
 The patient will take the first moxonidine tablet immediately during the visit after all 
the visit procedures are completed. The patient will be instructed to take 1 tablet of moxonidine 
0.4 mg in the morning, daily. The next visit will be scheduled in week 8 after the enrollment visit 
(in 56 days ± 5 days after the enrollment visit).  
The patient will be asked to bring all the blisters of investigated product (empty, started 
and not started blisters) to every visit after the study initiation. 
The investigator will give the patient blood pressure self-monitoring diary which is to 
be used by the patient to daily document her BP values and to bring it to every subsequent visit. 
3.6.3 Telephone visits (TV1 and TV2) 
Telephone visits are conducted at week 2 and week 4 after the enrollment visit. The 
investigator will document the disease history since the last visit, including all adverse events 
and changes in concomitant treatment.  
On the 2nd week telephone visit (TV1), the investigator evaluates efficacy, safety and 
tolerability of the investigated treatment. Patients will continue to take moxonidine 0.4 
mg/bisoprolol 5 mg until visit V2. If BP control is insufficient, the investigator may increase 
moxonidine and bisoprolol doses to 0.6 mg and 7.5 mg QD, respectively.   
On the 4th week telephone visit (TV2), the investigator evaluates efficacy, safety and 
tolerability of the investigated treatment. Patients will continue to take moxonidine 0.6 
mg/bisoprolol 5 mg until visit V2. If BP control is insufficient with moxonidine 0.6 
mg/bisoprolol 7.5 mg QD, the investigator adds perindopril 10 mg QD.   
 
3.6.4 Visit 2 (V2)  
Visit 2 is conducted at week 8 after the enrollment visit.  The investigator will 
document the disease history since the last visit, including all adverse events, changes in 
concomitant treatment, and changes in concomitant medications doses, if any.   
The investigator will analyze the effectiveness of the therapy according to the patient’s 
BP self-monitoring diary data.  
22 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The investigator measures blood pressure and heart rate in a sitting position after 5 
minutes of rest. Two measurements are done; the average value of the measurements is 
documented. BP is measured on the same arm during the entire study.  
The investigator analyzes the patient's compliance based on the number of returned 
tablets. 
The investigator evaluates response to the treatment (target BP reaching), documents it 
in source documents and decides on further treatment of the patient. If target BP has not been 
reached, the patient’s investigated product dose is titrated according to the study design. If the 
target BP has been reached, the patient continues with the current treatment until the next visit.  
The investigator will invite the patient to the next visit (visit V3) scheduled for week 24 
after the enrollment visit (168 days ± 5 days after the enrollment visit); the patient will be asked 
to return the investigated medication blisters (empty, started and not started blisters). The patient 
will be instructed to start taking the provided product the next day morning, 1 tablet per day. The 
patient will be instructed to report any adverse events (if applicable) to the investigator. 
 
3.6.5 Visit 3 (V3) 
The investigator will document the disease history since the last visit, including all 
adverse events, changes in concomitant treatment, changes in concomitant medications doses, if 
any.   
The investigator will analyze the effectiveness of the therapy according to the patient’s 
BP self-monitoring diary data.  
The investigator measures BP and HR according to the ESH/ESC recommendations that 
are listed in Appendix 1. Blood pressure and heart rate are measured in a sitting position after 5 
minutes of rest. Two measurements are done, the average value of the measurements is 
documented. BP is measured on the same arm during the entire study.  
Fasting blood sampling will be carried out for the following tests: BMP (potassium, 
sodium, creatinine, total calcium, inorganic phosphorus, ALT, AST), hormonal test (PTH) and 
bone metabolism tests, including osteocalcin, Ctx, OPG, RANKL. 
The investigator evaluates response to the treatment (target BP reaching), documents it 
in source documents and decides on further treatment of the patient. If target BP has not been 
reached, the patient’s investigated product dose is titrated according to the study design. If the 
target BP has been reached, the patient continues with the current treatment until the next visit.  
23 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The investigator analyzes the patient's compliance based on the number of returned 
tablets. The investigator will provide the patient with the investigated medications and invite the 
patient to the next visit (visit V4) scheduled for week 48 after the enrollment visit (336 days ± 5 
days after the enrollment visit); the patient will be asked to return the investigated medication 
blisters (empty, started and not started blisters). The patient will be instructed to start taking the 
provided product the next day morning, 1 tablet per day. The patient will be instructed to report 
any adverse events (if applicable) to the investigator. 
 
 
3.6.6 Final visit (V4)  
The investigator will document the disease history since the last visit, including all 
adverse events, changes in concomitant treatment, changes in concomitant medications doses, if 
any.  
The investigator will analyze the effectiveness of the therapy according to the patient’s 
BP self-monitoring diary data.  
The investigator measures BP and HR according to the ESH/ESC recommendations that 
are listed in Appendix 1.  Blood pressure and heart rate are measured in a sitting position after 5 
minutes of rest. Two measurements are done; the average value of the measurements is 
documented. BP is measured on the same arm during the entire study. Full physical examination 
is not required.  
Patient’s biochemical blood analysis (total calcium, inorganic phosphorus) is 
performed. Blood is sampled to investigate bone metabolism: osteocalcin, Ctx, OPG, RANKL. 
Blood is sampled to determine telomerase activity. 
Dual energy X-ray absorptiometry to determine BMD and detect osteopenia is 
performed. 
Applanation tonometry method is used to measure changes in patient’s PWV; duplex 
ultrasonography of extracranial brachiocephalic arteries is employed to evaluate IMT and 
subclinical atherosclerosis. 
 The investigator evaluates the response to the treatment (target BP reaching) and 
documents it in the source documents, as well as estimates patient compliance based on amount 
of the returned investigated product. 
24 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
After successful completion of visit V4 procedures, the patient completes her 
participation in the study. The investigated product is discontinued; further treatment is carried 
out according to the attending physician advice.  
3.7 Description of individual procedures 
Laboratory testing 
The investigator must warn a patient to come to the scheduled study visits after fasting 
to have her blood sampled for laboratory testing.  
Table 2. Method and frequency of laboratory testing 
Test  
Parameters 
Laboratory 
Method 
Frequency 
Blood biochemistry 
Creatinine* 
Potassium  
Sodium 
ALT 
AST 
Total calcium  
Inorganic phosphorus 
Site 
Adopted 
at 
the 
hospital 
center 
2x: visits V0 
and V3 
Blood biochemistry 
Total calcium  
Inorganic phosphorus 
Site 
Adopted 
at 
the 
hospital 
center 
3x: visits V0, 
and V3, V4 
Hormonal blood test  Parathyroid hormone  
Site 
Adopted 
at 
the 
hospital 
center 
1x: visit V1 
Bone metabolism  
Osteocalcin  
ɋW[ 
 
Site  
Adopted 
at 
the 
hospital 
center 
3x: visits V1, 
V3, V4 
OPG 
RANKL 
Site  
Adopted 
at 
the 
hospital 
center 
2x: visits V1, 
V4 
 
*Creatinine clearance (CC) is calculated by Cockcroft-Gault equation on visits V0 and 
V3:  
CrCl = (140 - age) x IBW / (Scr x 0,792)        (x 0.85 for females)  
If creatinine was measured in mg/dl, to convert the value to mkmol/L it should be 
multiplied by 88.4.  
 
25 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
3.8 Study products 
Investigated products, moxonidine and bisoprolol, will be provided by the Sponsor, 
packaged and labeled in accordance with local regulatory requirements. 
3.8.1 Investigated product: 
Name: I1-imidazoline receptor agonist, INN: moxonidine 
Manufactured by Rottendorf Pharma GmbH, Germany, packaged and released by   
Abbott Healthcare SAS, France  
Pharmaceutical form: 0.4 mg and 0.2 mg coated tablets manufactured by Rottendorf 
Pharma GmbH, Germany, packaged and released by Abbott Healthcare SAS, France. 
One tablet contains 0.40 mg moxonidine as an active substance and the following 
excipients: lactose monohydrate - 95.60 mg; povidone K25 - 0.70 mg; crospovidone – 3.00 mg; 
magnesium stearate - 0.30 mg; hypromellose 6mPas - 1.300 mg; ethyl cellulose aqueous 
Disp.30% - 4.000 mg (solids 1.200 mg) ; macrogol 6000 - 0.250 mg; talc - 0.875 mg; red ferric 
oxide (E172) - 0.125 mg; titanium dioxide (E171) - 1.250 mg. There are 14 tablets in the blister; 
the carton contains 1, 2 or 7 blisters. 
One tablet contains 0.20 mg moxonidine as an active substance and the following 
excipients: lactose monohydrate - 95.80 mg; povidone K25 - 0.70 mg; crospovidone – 3.00 mg; 
magnesium stearate - 0.30 mg; hypromellose 6mPas - 1.300 mg; ethyl cellulose aqueous 
Disp.30%- 4.000 mg (solids 1.200 mg); macrogol 6000 - 0.250 mg; talc - 0.9975 mg;  red ferric 
oxide (E172) - 0.0025 mg; titanium dioxide (E171) - 1.250 mg. There are 14 tablets in the 
blister; the carton contains 1, 2 or 7 blisters. 
Posology and method of administration: Moxonidine is taken orally, once-twice a 
day, regardless of meals. Maximum daily dose of moxonidine is 0.6 mg. 
Duration of treatment: Moxonidine 0.4 mg QD is prescribed to postmenopausal 
patients with hypertension and osteopenia. Subsequently, in patients with no response, the daily 
dose is titrated up to 0.6 mg; then perindopril 10 mg may be added to the regimen at week 8, if 
necessary. Patients should take the medication until study week 48 (V4). 
 
3.8.2 Comparative product  
Name: Cardioselective betaΌ blocker. INN: Bisoprolol. 
26 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Produced by Merck KGaA, Germany 
 Pharmaceutical form: film-coated tablets. 
 One tablet contains bisoprolol hemifumarate and bisoprolol fumarate (2: 1) as active 
substances 5 mg, and the following excipients: calcium hydrogen phosphate anhydrous - 132 
mg; corn starch fine powder - 14.5 mg; colloidal anhydrous silica - 1.5 mg; MCC - 10 mg; 
crospovidone - 5.5 mg; magnesium stearate - 0.97 mg, film coating: hypromellose 2910/15 - 2.2 
mg; macrogol 400 - 0.53 mg; dimethicone 100 - 0.11 mg; iron oxide yellow dye (E172) - 0.02 
mg; titanium dioxide (E171) - 0.97 mg.  
Posology and method of administration:  Bisoprolol is taken orally, once a day, 
regardless of meals.  
Duration of treatment:  Bisoprolol 5 mg is prescribed to postmenopausal patients with 
hypertension and osteopenia. Subsequently, in patients with no response, the daily dose is 
titrated up to 7.5 mg every 2 weeks; then perindopril 10 mg may be added to the regimen at 
week 8, if necessary. Patients should take the medication until study week 48 (V4). 
 
3.8.3 Additional medications  
3.8.3.1 Name: angiotensin converting enzyme inhibitor. INN: perindopril 
Produced by Les Laboratoires Servier Industrie 
 Pharmaceutical form: film-coated tablets. 
 One tablet contains perindopril arginine 10 mg as an active substance. Other 
ingredients: lactose monohydrate, magnesium stearate, maltodextrin, hydrophobic colloidal 
silica, sodium starch glycolate (type A), glycerol, hypromellose, macrogol 6000, titanium 
dioxide (E171), copper chlorophyllin (E141 II). 
Posology and method of administration:  once a day, orally, before a meal, preferably 
in the morning.  
Duration of treatment:  perindopril 10 mg is prescribed to postmenopausal patients 
with hypertension and osteopenia who have not reached target BP (<140/90 Hgmm) by V2 
(week 8).  Patients should take the medication until study week 48 (V4). 
 
3.8.4 Name: angiotensin II receptor blocker. INN: Losartan 
Produced by Berlin-Chemie, Germany. 
27 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Pharmaceutical form: coated tablets.  
Each tablet contains 50 mg of losartan.  
Posology and method of administration:  Bisoprolol is taken orally, once a day, 
regardless of meals. The product is prescribed to postmenopausal patients with hypertension and 
osteopenia non-responsive to moxonidine or bisoprolol monotherapy for 4 weeks and intolerant 
to perindopril. Patients should take the medication until study week 48 (V4). 
 
3.8.5. Name: calcium and vitamin D. INN: Calcium carbonate + cholecalciferol 
Produced by Nycomed Pharma, Norway. 
Pharmaceutical form: chewable tablets.  
Each tablet contains the following active ingredients calcium carbonate 1250 mg 
(equivalent to 500 mg of elemental calcium), cholecalciferol (vitamin DΎ) 5 mcg (200 IU) (as 
cholecalciferol concentrate - 2 mg),  excipients: sorbitol - 390 mg; isomalt - 62 mg; povidone - 
36.4 mg; magnesium stearate - 6 mg; aspartame - 1 mg; orange oil - 0.97 mg; mono- and 
diacylglycerols - 0.0008 mg. 
 
Posology and method of administration:  the product is taken orally during meals, it 
should be chewed or dissolve in the mouth.  
 
3.9 Product packaging and storage 
3.9.1 Packaging.  
Moxonidine is packaged in original factory blisters; every blister contains 14 tablets.  
Bisoprolol is packaged in original factory blisters; every blister contains 10 tablets 
either every blister contains 50 tablets.  
At every visit (V1, V2, V3), the investigator will provide a patient with the product 
blisters for subsequent treatment period till next visit. 
Storage conditions. Moxonidine and bisoprolol do not require any special storage 
conditions. 
 
28 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
3.9.2 Products counting procedures 
The investigator analyzes the patient's compliance based on the number of returned 
tablets at visits 2, 3 and 4. 
 
3.10 Study endpoints 
Primary endpoint: 
x 
Changes in mean values of the bone resorption marker (collagen type 1 C-
telopeptide) at the end of the study (V4) from the baseline (V1) in comparison between the 
groups. 
Secondary Endpoints:  
x 
To assess mean values of osteocalcin at visit 4 versus baseline level (visit 1) and 
to compare the values between the groups   
x 
To assess mean values of the receptor activator of nuclear factor kappa-B ligand 
(RANKL) at visit 4 versus baseline level (visit 1) and to compare the values between the groups   
x 
To assess mean values of BMD at visit 4 versus baseline level (visit 1) using 
control dual-energy X-ray absorptiometry and to compare the results between the groups   
x 
To assess mean telomerase activity at visit 4 versus baseline level (visit 1) and to 
compare the values between the groups   
x 
To assess mean pulse wave velocity (PWV) at visit 4 versus baseline level (visit 
1) and to compare the values between the groups   
x 
To assess mean intima-media thickness (IMT) at visit 4 versus baseline level (visit 
1) and to compare the values between the groups   
x 
To estimate the proportion (%) of patients who achieved target blood pressure 
<140/90 mmHg at the visit 2 (Week 8), 3 (Week 24) and 4(Week 48) and according to the 
patient's diary. 
29 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
4 PATIENT SCREENING AND EXCLUSION 
4.1 Patient Population 
Postmenopausal women with essential hypertension and osteopenia treated with 
moxonidine. 
4.2 Inclusion criteria  
A patient should meet all of the following inclusion criteria: 
1. 
Females aged 45 years and older 
2. 
Postmenopausal (absence of menstrual periods for a minimum of 12 months) at the 
moment of Informed Consent sign. 
3. 
$UWHULDOK\SHUWHQVLRQJUDGH,,,SHU(6+(6&JXLGHOLQHVGLDVWROLFSUHVVXUH
and <11PP+JV\VWROLFSUHVVXUHDQGPP+J. 
4. 
Not achieving BP targets <140/90 mmHg either during antihypertensive therapy or naive.  
5. 
Absence of moxonidine or bisoprolol treatment at least 6 months before the study 
6. 
Osteopenia of lumbar spine and/or proximal part of the femur (osteoporosis T-score from 
-1 to -2.5 standard deviations [SD]) by X-Ray densitometry. 
7. 
.Signed informed consent form to participate in the program. 
4.3 Exclusion criteria  
A patient must not meet any of the following exclusion criteria: 
1. Hypersensitivity to moxonidine, bisoprolol or any other ingredient of the respective 
formulations 
2. Any Contraindications for moxonidine, bisoprolol  
3. 2VWHRSRURVLVɌ-score below - 2.5 SD). 
4. Primary or secondary hyperparathyroidism. 
5. Paget’s disease of bones. 
6. History of low traumatic bone fractures. 
7. Malabsorption syndrome. 
8. History of gastro-intestinal surgery. 
9. Severe disturbance of peripheral circulation.  
10. Raynaud’s disease. 
11. Symptomatic (secondary) hypertension (caused by any primary internal diseases)  
30 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
12. Morbid obesity (BMI over 40 kg/m2). 
13. Symptoms of estrogen deficiency such as hot flushes, nights sweat, vaginal dryness 
14. Administration of any hormone-replacement therapy (HRT) or  intake of isoflavones 
15. Secondary hypogonadism. 
16. 6LVW%3PP+JDQGRU'LDVW%310 mm Hg. 
17. Clinical presentations of cardiovascular disease: coronary heart disease (CHD), history of 
stroke, transient ischemic attack (TIA), Charcot’s syndrome. 
18. Severe heart failure.  
19. Hemodynamically significant congenital heart disease. 
20. Heart rhythm disorders which require permanent use of any antiarrhythmic medications 
LQFOXGLQJȕ-adrenoblockers and calcium antagonists). 
21. Diabetes mellitus of any genesis. 
22. Severe liver failure. 
23. Severe kidney failure including patients on dialysis 
24. Thyroid diseases accompanied by functional disorders (thyrotoxicosis or uncompensated 
hypothyroidism).  
25. Alcohol and drug abuse. 
26. Patients with oncological diseases diagnosed within 5 years before IC execution. 
27. Inability of the patient to comprehend the essence of the program and to provide his/her 
consent for participation in the program. 
28.  Patients with any condition, which in the opinion of the Investigator makes the patient 
unsuitable for inclusion based on clinical judgment. 
29. Corticosteroid therapy 
30. Participation in any other clinical study during the whole course of this investigation 
including participation in a study within 30 days prior to providing the informed consent for 
this trial 
4.4 Start of treatment criteria  
Start of investigated treatment (i.e., patient enrollment to the study) is possible when all 
of the following conditions are met during the enrollment visit: 
1. 
Patient is to meet all the inclusion criteria and should lack any of the exclusion 
criteria. 
31 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
2. 
Patients previously treated with antihypertensive agents have undergone 7-10-day 
washout period according to the protocol (all antihypertensive drugs are discontinued, except 
fast-acting agents to relieve hypertensive episodes). 
4.5 Study withdrawal criteria   
A patient may be withdrawn from the study before the treatment is started, if the 
investigator discovers deviations from any inclusion criteria, exclusion criteria, or criteria for the 
treatment initiation. Patients who withdrew before the treatment start (i.e., during screening or 
washout period), will be substituted with new patients.  
In the present study, withdrawal from the study will also mean discontinuation of the 
investigated treatment. 
The patient may be withdrawn from the study due to the following reasons: 
1. 
Withdrawal of the informed consent to participate in the study. 
2. 
Low treatment compliance (<80%). 
3. 
Adverse events that in the investigator’s opinion make the treatment continuation 
impossible, dangerous, or inconsistent with best patient interest and safety. A SAE is not 
necessarily the cause of early patient withdrawal from the study. 
4. 
According to the investigator, continued participation of the patient in the study 
threatens the patient’s safety.  
5. 
It is necessary to administer treatment prohibited by the study protocol. 
6. 
Failure of the investigated treatment (i.e., recurrent rise of blood pressure 
PP+JDIWHUSUHYLRXVO\DFKLHYHGWDUJHW%3OHYHO 
7. 
Death of the patient.  
8. 
Sponsor decision. 
4.6 Early withdrawal procedures 
All patients who were withdrawn from the study early are asked to complete the final 
visit procedures, if possible. If the decision to terminate the patient participation was made 
between two scheduled visits, the patient is asked to come for the upcoming scheduled visit, as 
usual, or make an unscheduled visit. 
The reason for the early withdrawal should be indicated in the source documents. If the 
patient is lost to follow-up, the investigator should make all reasonable efforts to contact the 
32 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
patient to obtain information on date of withdrawal and reason for the investigated product 
discontinuation.  If the patient cannot be reached, she will be considered as lost to follow-up. 
In the case of early investigated product discontinuation due to an adverse event 
(regardless of whether the event should be immediately reported), the researcher must make 
every effort to collect information regarding the AE outcome. This information is added to the 
source documents and CRF, under adverse events section.  
 
5 Treatment of patients  
5.1 Prescribed treatment 
Treatment assignment at the study visits 
Washout period is designed for patients who have already been taking antihypertensive 
medications. All antihypertensive medications are discontinued 7-10 days prior to the enrollment 
visit. The patient is asked to refrain from taking these and any other antihypertensive 
medications during the washout period. The average duration of the washout period is 7 days. 
The investigator may shorten the duration of the washout period, but it should not be shorter than 
6 half-life periods (T 1/2) of the antihypertensive medications patient was taking.   
During the washout period, the patient may be administered with fast-acting agents to 
relieve hypertensive episodes (at the investigator’s discretion – nifedipine, captopril). The period 
from the last dose of these antihypertensives to the enrollment visit must be at least 6 T1/2 of 
these agents (e.g., 18 hours for nifedipine).  
If the above conditions are not met, the patient is withdrawn from the washout period 
and will not participate in the study. The researcher may at any time terminate the washout 
period, if the patient does not tolerate it well.  
The washout period is not required for patients who were not previously treated with 
antihypertensives, and patients who were not receiving antihypertensives at the time of the 
screening. If the patient was treated with any antihypertensives earlier and discontinued the 
medications before the screening, the washout period is not necessary for her, if the period 
between the last dose of the antihypertensives and the enrollment visit is not shorter than 6 T1/2 
of these drugs.  
 
33 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
All enrolled patients are randomized in the two study groups (moxonidine group or 
bisoprolol group). 
All group 1 patients are prescribed with moxonidine 0.4 mg monotherapy. At the V1 
enrollment visit, the patient will be given the medication and will take first dose of moxonidine 
in the presence of the investigator. Thereafter, patients will take the medication every morning, 
during the entire study. The medication will be dispensed to a patient at visits V1, V2, V3, and 
the patient will start taking the drug on her own on the day following the visit. One tablet of the 
investigated product should be taken daily, in the morning, regardless of meals.  
On 2nd week telephone visit, the investigator evaluates efficacy, safety and tolerability 
of the investigated treatment. Patients will continue taking moxonidine 0.4 mg QD until next 
visit V2. If BP control is insufficient, the investigator may increase moxonidine dose to 0.6 mg 
QD.   
On 4th week telephone visit, the investigator evaluates efficacy, safety and tolerability 
of the investigated treatment. Patients will continue taking moxonidine 0.4 mg (0.6 mg) QD until 
next visit V2. If BP control is insufficient with moxonidine 0.6 mg QD, the investigator adds 
perindopril 10 mg QD.   
 
All group 2 patients are prescribed with bisoprolol 5 mg monotherapy. At the V1 
enrollment visit, the patient will be given the medication and will take first dose of bisoprolol in 
the presence of the investigator. Thereafter, patients will take the medication every morning, 
during the entire study. The medication will be dispensed to a patient at visits V1, V2, V3, and 
the patient will start taking the drug on her own on the day following the visit. One tablet of the 
investigated product should be taken daily, in the morning, regardless of meals.  
On 2nd week telephone visit, the investigator evaluates efficacy, safety and tolerability 
of the investigated treatment. Patients will continue to take bisoprolol 5 mg until visit V2. If BP 
control is insufficient, the investigator will increase bisoprolol dose to 7.5 mg QD.   
On 4th week telephone visit, the investigator evaluates efficacy, safety and tolerability 
of the investigated treatment. Patients will continue to take bisoprolol 5 mg (7.5 mg) until next 
visit V2. If BP control is insufficient with bisoprolol 7.5 mg QD, the investigator adds 
perindopril 10 mg QD.   
 
At visit V2: 
34 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
x 
If a patient responds to the selected treatment regimen (BP <180/120 mmHg), the 
investigator will continue this regimen until the next visit. 
x 
,I D SDWLHQW GRHV QRW UHVSRQGWR WKH VHOHFWHG WUHDWPHQW UHJLPHQ %3 180 /120 
mmHg), the patient is withdrawn from the study. 
 
At visit V3: 
x 
If a patient responds to the selected treatment regimen (BP <180/120 mmHg), the 
investigator will continue this regimen until the next visit. 
x 
,I D SDWLHQW GRHV QRW UHVSRQG WR WKH VHOHFWHG WUHDWPHQW UHJLPHQ %3 180/120 
mmHg), the patient is withdrawn from the study. 
At final visit V4, the investigator will evaluate the patient response to the treatment and 
will discontinue all investigated medications. Further treatment is carried out according to the 
attending physician advice. 
5.2 Fast-acting agents to relieve hypertensive episodes 
During the washout period and the rest of the study, use of short-acting agents to relieve 
hypertensive episodes, such as captopril and nifedipine, is allowed. However, patients must be 
instructed to refrain from these medications for 24 hours prior to the study visit in order to obtain 
accurate blood  pressure data. At the visits, the investigator will ask if a patient took any short-
acting drugs to relief hypertensive episodes; data and time of the last dose will be documented in 
the CRF. 
5.3 Investigated treatment withdrawal  
If the investigated treatment should be withdrawn for any reason before the end of the 
study, gradual investigated products doses reduction is not required. The early treatment 
withdrawal means the patient is withdrawn from the study.  
5.4 Permitted and prohibited treatment 
5.4.1 Permitted treatment  
Patients with comorbidities may continue taking previously prescribed medications. 
Patients will be asked to report any medications and dietary supplements they were taking within 
a month prior to the screening or have taken during the study. The investigator will document 
any medication the patient is taking in the source documents and CRF. 
35 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Additionally, it is recommended to avoid nonsteroidal anti-inflammatory drugs, 
including selective cyclooxygenase-2 inhibitors, and ascorbic acid at a dose >3 g/day due to the 
increased risk renal function impairment. 
5.4.2 Prohibited treatment 
During the treatment with the investigated product, patients should not take: 
x 
Other antihypertensive drugs, except for the investigated products. The only 
exception is short-acting antihypertensives prescribed by the investigator to relieve hypertensive 
episodes PRN.  These medications should be withheld the day prior to the visit to avoid effects 
on blood pressure measurement during the visit and evaluation of the investigated treatment 
efficacy.  
x 
Thiazide diuretics, corticosteroids, bisphosphonates or levothyroxine since these 
agents are known to affect bone metabolism and BMD. 
x 
Antacids, if the interval between an antacid and the investigated product 
administration is less than 2 hours. 
If there is a need to prescribe the prohibited treatment to a patient or it became known 
that a patient is receiving the prohibited treatment, the patient is withdrawn from the study. 
5.5 Analysis of compliance 
At every visit, starting with visit V2, the dispensed and returned investigated product is 
counted, and the patient compliance is assessed. The investigator or his/her authorized 
representative will count the number of dispensed and returned tablets and document it in the 
accountability form and CRF. Additionally, date of the first and last product administration, and 
deviations in the product dosing regimen within the last intervisit interval (if any) will be 
documented in CRF. 
In case of low patient compliance with the investigated treatment (the patient took <80 
tablets within the intervisit interval), the patient will be withdrawn from the study. 
5.6 Patient supply and return of the product  
The investigated products moxonidine and bisoprolol are intended only for patients 
participating in the study and should be used according to the protocol.  
The patient will be provided with the required amount of the product at the enrollment 
visit (V1), visit V2, and visit V3 for subsequent treatment period till next visit.   
36 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The product will be provided to the patient in the course of the study only. The 
treatment will be discontinued at final visit V4. 
The patients will be asked to bring all used and unused investigated products blisters to 
the study site at visits V2, V3, V4. 
All defects and damages of the investigated product or its packaging must be reported to 
the study CRA. Additionally, the investigator must report any patient complaints to the study 
CRA (change in the product taste, appearance, etc.). 
5.7 Product accountability 
The investigator and/or pharmacist and/or authorized site staff is responsible for the 
product accountability. The product accountability will be monitored by the CRA on a regular 
basis. 
Sponsor will provide the investigated product accountability forms to document all the 
product shipments, distribution and return. The investigator and/or pharmacist and/or authorized 
site staff should fill out these forms in a timely manner. CRA must fill out the product return and 
disposal form after the end of the study. 
 
6 EFFICACY EVALUATION  
Efficiency analysis will be carried out in the population of patients who completed the 
study according to the protocol.  
 
6.1 
Primary endpoint efficacy criteria:  
Changes in mean values of the bone resorption marker (collagen type 1 C-telopeptide) 
at the end of the study (V4) from the baseline (V1) in comparison between the groups. 
  
6.2 
Secondary endpoints efficacy criteria:  
1. 
Changes in mean values of the bone synthesis marker (osteocalcin) at the end of 
the study (V4) from the baseline (V1) and to compare the values between the groups. 
2. 
Changes in mean values of the receptor activator of nuclear factor kappa-B ligand 
(RANKL) at visit 4 versus baseline level (visit 1) and to compare the values between the groups   
37 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
3. 
Changes in mean values of BMD at visit 4 versus baseline level (visit 1) using 
control dual-energy X-ray absorptiometry and to compare the results between the groups   
4. 
Changes in mean values of  telomerase activity at visit 4 versus baseline level 
(visit 1) and to compare the values between the groups   
5. 
Changes in mean values of  pulse wave velocity (PWV) at visit 4 versus baseline 
level (visit 1) and to compare the values between the groups   
6. 
Changes in mean values of intima-media thickness (IMT) at visit 4 versus 
baseline level (visit 1) and to compare the values between the groups   
7. 
Proportion of the treatment responders (defined as the proportion (%) of patients 
who achieved target blood pressure <140/90 mmHg) after 8 and 48 weeks of the investigated 
treatment (V2, V3 and V4) and to compare the values between the groups. 
 
7 SAFETY EVALUATION 
7.1 Safety parameters  
The safety parameters that are measured at every study visit are shown in Table 2. The 
investigator will collect required data including: 
1) 
documentation of significant medical history at the screening visit the following 
visits,  
2) 
identification and documentation of adverse events, including abnormalities 
identified with: 
a) 
physical examination,  
b) 
laboratory tests. 
The investigator will collect and interpret all relevant information and make a decision 
on whether to report any deviation from the norm, as an adverse event. 
7.2 Methods and timing 
Methods and timing of the parameters identification are as follows: 
Physical examination. During the patient screening and enrollment and at the final 
visit, the investigator will document the patient's complaints and abnormalities, detected on 
38 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
physical examination. All clinically significant abnormalities should be reported as adverse 
events. 
Blood pressure and heart rate. All patients will have their blood pressure and heart 
rate measured at every visit. If blood pressure and heart rate are abnormal, the investigator will 
evaluate the clinical significance of the abnormality and decide on whether to document it as an 
adverse event. 
Laboratory tests parameters: creatinine (including creatinine clearance calculation 
according to Cockcroft-Gault equation), potassium, sodium, ALT, AST. Fasting blood samples 
will be obtained at screening and at the final visit. Results of the tests will be entered into the 
CRF. If the sample is lost, the investigator may order resampling if medically indicated (e.g., if 
invalid test results are suspected). 
All clinically significant adverse deviations from the baseline (screening) will be 
reported as adverse events. 
8 ADVERSE EVENTS 
Definitions 
8.1 Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, including laboratory parameters deviations. AE does not 
necessarily have a causal relationship with the treatment.  
Causal relationship with investigated treatment  
The AE(s) relationship with investigated product(s) will be assessed according to the 
following categories: 
1. The relationship is considered certain if an AE developed during the treatment with 
the product and cannot be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must 
be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure if necessary.  
2. The relationship is considered probable if an AE occurred in a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other 
39 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge).  Rechallenge information is not required to fulfil this definition.  
3. The relationship is considered possible, if an AE occurred in a reasonable time 
sequence to administration of the drug, but which could also be explained by concurrent disease 
or other drugs or chemicals.  Information on drug withdrawal may be lacking or unclear.  
4. The relationship is considered unlikely, if a causal relationship of an AE with the 
drug cannot be ruled out, but:   
- other drugs, chemicals or underlying disease provide plausible explanations,  
- temporal relationship of the AE to the drug administration is improbable.  
5. AE is considered unrelated to the drug administration, if: 
- there is a clear alternative explanation of the AE, and/or 
- temporal relationship of the drug and the AE is groundless, and/or 
- relationship of the drug with the AE is not plausible.  
6. The relationship is considered unassessable, if the data is insufficient or 
contradictory and cannot be supplemented or verified.  
8.2 Adverse reaction (AR) 
Adverse reaction (AR) means a noxious and unintended response to an investigated 
medical product, associated with any dose of the product.  
According to the “Detailed guidance on the collection, verification and presentation of 
adverse reaction reports arising from clinical trials on medicinal products for human use" (April 
2006), all adverse events, regarded by an investigator or Sponsor as having reasonable causal 
relationship with the medicinal product are considered AR, that is related to the investigated 
product. 
Based on the above definitions, ARs are all AEs with the following relationship with the 
investigated product:  
1 - Certain 
2 - Probable  
3 - Possible  
4 - Unassessable 
40 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
 
AE is not considered AR if relationship with the drug is estimated as:  
5 - Unknown 
6 - Unrelated  
 
Seriousness criteria  
AE/AR is considered serious if it: 
x 
Results in death, 
x 
Is a life-threatening event; 
Note: AE is not considered to be life-threatening if the subject’s life was in danger 
during the AE; this does not apply to events that hypothetically could have led to death if they 
progressed.  
x 
Requires inpatient hospitalization or prolongation of an existing hospitalization; 
x 
Leads to persistent and significant disability or incapacity; 
x 
Is a congenital anomaly or birth defect; 
x 
Is an important from a medical point of view event that may pose a risk to the 
patient or may require intervention to prevent one of the outcomes described above. All 
suspected cases of infectious agents transmission via medicinal product are considered serious 
and should be evaluated in the category of “medically significant events” if there are no other 
seriousness criteria. 
 
AE/AR is not considered serious if: 
x 
The event does not meet conditions described in the definition of serious AE/AR. 
 
Adverse event (AE) / adverse reaction (AR) severity  
The severity of serious and non-serious AE or AR should be evaluated according to the 
following criteria. 
x 
Mild: no intervention or routine actions are required; for laboratory parameters, 
abnormality is considered mild. 
x 
Moderate: no intervention or routine actions are required; for laboratory 
parameters, abnormality is considered moderate. 
41 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
x 
Severe: intervention or routine actions are required; for laboratory parameters, 
abnormality is considered severe. 
 
Adverse event (AE) / adverse reaction (AR) expectedness criteria 
AE/AR is considered unexpected, if its nature, seriousness or outcome does not 
correspond with the Reference safety document (there must be ONLY ONE Reference safety 
document defined by the Protocol, and Clinical trial appendices; it should be referred to in the 
protocol and appendix cover letters).  
If the product has already been issued a registration certificate (RC), the Reference 
safety document is the Summary of product characteristics (SPC). If there are multiple versions 
of the SPC (e.g., if there are national product RCs), the most appropriate version of the SPC 
should be provided.  
If the product has never been issued with a registration certificate, the Reference safety 
document is the Investigator's Brochure (IB).  
 
8.3  Suspected unexpected serious adverse reaction (SUSAR) 
Any serious unexpected adverse events, considered by an Investigator or Sponsor as 
associated with the product are qualified as unexpected AR (SUSAR). SUSARs should be 
reported according to the instructions in Section 8.4. 
 
8.4 Adverse events monitoring and reporting 
At each study visit, the investigator will assess any subjective or objective AEs. AEs 
identified based on complaints of a patient, patient’s relatives/legal representatives, over phone, 
in writing or by e-mail will also be documented. In such cases, the investigator should try to 
assess the AE and obtain medical conformation.  
In case of AE, the investigator must document the AE in the special CRF section 
“Adverse event form”; a new page should be used for every AE, the investigator should assess 
causal relationship of the AE and the product regardless of whether the AE is serious or not, 
whether it is associated with the drug, discovered by the investigator or patient.  
42 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
All available information and results of diagnostic procedures (laboratory, instrumental 
tests, etc.) should be documented and/or attached to the CRF. 
The investigator must monitor SAE for the entire study duration (including the follow-
up period) until the outcome.  
The investigator must monitor cases of pregnancies that occurred while on treatment 
with the investigated treatment or during follow-up period and document any congenital 
abnormalities.  
 
Reporting requirements   
The investigator must report SAEs (both related and unrelated to the investigated 
product) by faxing the CRF Adverse Event Form pages no later than 24 hours after he/she 
became aware of the SAE:  
If safety issues are dealt with directly by Sponsor: 
Sponsor medical expert O.N. Tkacheva, 
tel. +7(495)210-73-27, mob. +7(985)211-85-23 
tkacheva@rambler.ru 
All serious adverse events must be monitored until the outcome.  
 
Any information and required documents that may be available (copies of results of 
laboratory tests, procedures, autopsy, cause of death data, etc.) will be provided by the 
Investigator by means of separate written reports directly to the Sponsor medical expert as soon 
as possible. 
The investigator should comply with applicable local regulations for AR reporting to 
regulatory authorities/ethics committees.  
Safety Reporting to Abbott. 
(a) Institution and Investigator shall comply with all applicable regulations with respect to 
the documentation, assessment, and reporting of safety data, including but not limited to 
the submission of expedited and periodic reports to the appropriate regulatory authorities 
and Ethics Committees. 
43 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
(b) In addition, in an effort to assist Abbott with its obligation to collect world-wide safety 
information with respect to the Study Product(s), Institution and Investigator shall report 
to Abbott: 
(i) 
all periodic reports regarding the Study contemporaneously with corresponding 
submissions to authority(ies); 
(ii) any safety issues related to the Study; 
(iii) any safety signal associated with the Abbott Product(s); 
(iv) interim Study reports, if applicable; and 
(v) the final Study report and/or or the corresponding publication addressing safety data 
and findings. 
(c) The above mentioned safety information and reports shall be provided by Institution or 
Investigator to Abbott’s Pharmacovigilance department.    
(d) Abbott is obliged to provide Institution and/or Investigator with the current information 
on the safety and efficacy of the Study Material as described in the most current version 
of the Summary of Product Characteristics. 
(e) The parties agree to exchange certain safety related information with respect to the 
Study Materials without delay, including but not limited to new risks, safety variations, 
any regulatory action based on safety reasons, or any voluntary activity by the parties 
due to safety reasons. 
(f) 
Failure of Institution or Investigator to transmit such reports and/or information as 
mentioned above in a timely manner may result in withholding of further shipment of 
Study Materials and/or withholding of Study funding. 
(g) All Pharmacovigilance-relevant information mentioned above relating to the Abbott 
Product(s) shall be reported to the following contact: 
x Alexey Ryakhin, MD, Pharmacovigilance Manager / ASR 
Abbott Laboratories LLC 125171, Moscow, Russia 16a Leningradskoe Highway, Building 
1, floor 6. 
Tel:+7(495) 258-42-80 ext. 57478 
Fax:+7(495) 258-42-81 
Mobile/Cell: +7 (926) 101-49-64 
e-mail : aleksey.riahin@abbott.com 
x Anton Pisarikhin, Pharmacovigilance Specialist / ASR back-up  
44 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Abbott Laboratories LLC 125171, Moscow, Russia 16a Leningradskoe Highway, Building 
1, floor 6. 
Tel:+7(495) 258-42-80 ext. 57478 
Fax:+7(495) 258-42-81 
Mobile/Cell: +7 (926) 197-99-66 
e-mail : anton.pisarihin@abbott.com 
8.5 Sponsor responsibilities for AE reporting  
The sponsor should ensure that all necessary information about suspected serious and 
suspected unexpected serious adverse reactions (SUSAR) is duly reported to the regulatory 
authorities and to Ethics Committees within the appropriate time period after the sponsor became 
aware of the event (the day when the Sponsor received a SUSAR report): 
 - fatal and life-threatening unexpected events - not later than 7 days; 
 - other unexpected serious events - not later than 15 days.  
The sponsor should ensure that in case any further information about the event becomes 
available, all the required data and supporting documents (which may become available in the 
future) is also duly reported within the time period specified above.  
 
9 DATA MANAGEMENT AND RECORD-KEEPING 
9.1 Data collection and processing 
The investigator must fill out Case Report Forms (CRFs) according to the instructions 
obtained before the start of the study. Paper CRF will be used in the study. The investigator must 
store a copy of a CRF along with other study documents in a place with restricted access. All 
data documented in CRFs must be supported by the data in the patient source documents. 
CRF data will be entered into the integrated database by authorized personnel in 
accordance with internal Sponsor SOPs. Double data entry will be employed. All data will be 
systematically analyzed for errors and inaccuracies. Data that need clarification is entered into 
special forms and sent to the site for clarification. After questionable data is clarified, copies of 
the signed forms must be stored in the CRF and the originals must be provided to the data 
managing staff.  
45 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The database will be locked after all questionable data are verified, and it is confirmed 
that the entered data are complete and accurate. 
Statistical analysis will be conducted under the supervision of a responsible 
biostatistician according to prespecified statistical analysis plan (please refer to “Statistical 
analysis”).  
9.2 Data recording  
The investigator is required to maintain source documents for every study participant, 
containing demographic and medical data, including results of protocol-specified investigations. 
All information contained in CRFs should match the source documents. The investigator must 
fill out a CRF based on patient's medical record and should store the study documents, including 
informed consent form, the protocol, the investigator's brochure, and all protocol amendments in 
a room with restricted access.  
9.3 Archiving 
The investigator must ensure appropriate documentation storage for at least 15 years 
after the end of the study. Disposal of the study documents is possible with the Sponsor written 
permission. The sponsor should inform the investigator in writing about the expiration of the 
documentation storage term.  
Key documents (that allow evaluating the study conduct and quality of the data 
obtained) should be stored in a way that ensures their integrity and complete security for the 
entire storage term, and also guaranties their availability on request from competent authorities. 
The key documents include: 
x 
Written approval of the study protocol with all amendments by Ethic Committee 
x 
All source documents and results of investigations  
x 
Patient informed consent forms (with protocol number and study name) 
x 
Any other documentation relevant to the study. 
 
46 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
10 STATISTICS  
Statistical Analysis 
10.1 General methods of analysis 
Statistical analysis will be conducted under the supervision of a responsible 
biostatistician. The details of statistical analysis will be provided in the statistical analysis plan in 
accordance with the GCP requirements and other relevant requirements and laws. The statistical 
analysis plan will be finalized before the data lock point. All deviations from the final statistical 
plan version will be justified in the final program report.  
The results will be combined for the complete study sample. Two-sided levels of 
significance and confidence intervals will be calculated. The significance of differences will be 
calculated for two-sided tests, with a critical significance level of 0.05.  
For parameters of interval scale type, the following will be calculated: the arithmetic 
mean (95% confidence interval for the mean), standard deviation, median, 25th and 75th 
percentiles. For parameters of ordinal scale type, median, 25th and 75th percentiles will be 
calculated. For parameters of nominal scale type, frequency categories and confidence intervals 
for the frequencies (modified Wald method) will be calculated. If the assumptions made during 
the preliminary study planning are found to be erroneous, the analysis methods will be modified 
to conduct a more suitable analysis.  The result of the primary endpoint analysis will be 
presented as an absolute number and proportion (%) of patients with target BP (<140/90 mm Hg) 
achieved at visit V4. 
Statistical analysis will be carried out using SPSS/PASW Statistics software package 
(version 18), SPSS Inc., Chicago, Illinois, USA. 
10.2 Procedures for accounting for missing, unanalyzable and questionable data 
In case of missing, unanalyzable and questionable data appropriate statistical methods 
will be applied. Patients who did not complete the planned treatment course will be added to the 
analysis by the last observation carried forward method.  
Patient population for statistical analysis 
The following patient populations will be used for the statistical analysis: 
Intention-to-treat population (ITT): all enrolled patients with investigations data from 
visits V3 or V4, excluding the enrollment visit. 
47 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
Per protocol patient population (PP): patients who completed the study according to 
the protocol. 
Analysis of demographics, disease data, concomitant therapy, and other baseline 
data 
Demographic data (age, gender), the initial condition data (height, weight, body mass 
index) will be presented along with a summary in the form of a rate or percentage, or by using 
the mean, standard deviation, median, interquartile range, minimum and maximum, depending 
on the type of the variable. 
10.3 Efficacy Analysis 
Efficiency analysis will be carried out in the population of patients who completed the 
study according to the protocol (PP).  
The main indicator of the treatment efficiency: 
Changes in mean values of the bone resorption marker (collagen type 1 C-telopeptide) 
at the end of the study (V4) from the baseline (V1) in comparison between the groups. 
Secondary efficiency indicators:  
x 
Changes in mean values of telomerase at the end of the study (V4) from the 
baseline (V1). 
x 
Changes in mean values of Hs-CRP, lipids, PWV and IMT at the end of the study 
(V4) from the baseline (V1). 
x 
Changes in mean values of the bone synthesis and resorption markers 
(osteocalcin, collagen type 1 C-telopeptide) at the end of the study (V4) from the baseline (V1). 
x 
Changes in mean values of the bone synthesis marker (osteocalcin) at the end of 
the study (V4) from the baseline (V1). 
x 
Changes in mean values of the receptor activator of nuclear factor kappa-B ligand 
(RANKL) at the end of the study (V4) from the baseline (V1). 
x 
Changes in mean values of BMD at the end of the study (V4) from the baseline 
(V1). 
48 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
x 
Proportion of the treatment responders (defined as the proportion (%) of patients 
who achieved target blood pressure <140/90 mmHg) after 8, 24 and 48 weeks of the investigated 
treatment (V2, V3 and V4). 
The treatment efficacy will be evaluated on visits V2, V3 and V4 based on SBP and 
DBP measurements. Clinical response to the treatment is defined as follows:  
x 
Responders: hypertension control, if BP <140/90 mmHg at the visit. 
x 
Non-UHVSRQGHUVXQFRQWUROOHGK\SHUWHQVLRQLI%3PP+JDWWKHYLVLW 
The efficacy results will be presented using descriptive statistics. Historical control 
(publications data) will be used to interpret the results.  
10.4 Safety analysis 
All safety data will be analyzed in the safety analysis population. Safety analysis 
includes identification of all adverse events, including serious adverse events at every visit 
following the screening. 
Analysis of adverse events including serious adverse events will be conducted to 
determine the total number of AEs, the total number of patients with adverse events, the number 
of treatment-related adverse events, the number of AEs associated with product discontinuation 
and the number of voluntary withdrawal of informed consent. 
Rate and severity of all adverse events and drug-related adverse events (i.e., at least 
“possibly” associated with the studied product) will be summarized by organ systems. Data on 
the product withdrawal due to adverse events will be summarized in tables. The safety results 
will be presented using descriptive statistics. 
Interim Analysis 
No interim analysis will be performed for this study. 
10.5 Sample size rationale 
As this is an explorative study with open design no formal sample size calculation was 
performed. The focus of the study is to obtain scientific data for a publication and taking into 
account a reason of feasibility of enrollment to timelines and screening of 300 patients per year 
in assumption that ratio of screened / enrolled patients is approximately 3 to 1  so it is expected 
that not less than 100 patients but no more than 114 patients will be enrolled in the study. 
According to this approach the total sample size is chosen 114 subjects. 
49 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
.10.6 Direct access to source data/documents 
The investigator must provide direct access to source data and source documents to 
CRAs and other sponsor representatives, auditors, Ethics Committees and regulatory authorities 
representatives. 
 
11 QUALITY CONTROL AND ASSURANCE 
This study will be conducted in compliance with the principles and requirements 
specified in the following documents: 
- Declaration of Helsinki regarding medical research on humans (recommendations for 
physicians on biomedical research involving human subjects, Helsinki 1964, amendments Tokyo 
1975, Venice 1983, Hong Kong 1989, Somerset West 1996, Edinburgh 2000, Washington 2002, 
Tokyo 2004, Seoul 2008). 
- ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996,   
and in accordance with local regulatory requirements. 
By signing the protocol, the investigator agrees to comply with the instructions and 
procedures described in the protocol and, thereby, to comply with the principles of Good Clinical 
Practice followed by the protocol. A copy of the Declaration of Helsinki will be kept in the 
investigator’s folder in every study site. 
Audit, inspection 
In order to ensure compliance of the study with GCP and regulatory requirements, the 
study may be audited by external organizations, or regulatory authorities, in addition to sponsor 
monitoring. In the case of audit/inspection, the investigator must provide the auditors with access 
to any study related documents.  
 
12 ADMINISTRATIVE ISSUE 
12.1 Changes to the study protocol   
Any protocol changes are made in the form of a written amendment which must be 
signed by Sponsor and investigator before it comes into effect. For amendments affecting 
50 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
subject’s security, study objectives or scientific content, additional approval by Ethics 
Committees is required.  
Changes affecting only administrative aspects of the study (addresses, phone numbers, 
minor changes in the investigated product packaging) do not require formal registration as an 
amendment or Ethics Committees approval, but these organizations are informed about the 
administrative changes.  
12.2 Early study termination 
Early termination of the study and/or a study site may occur by Sponsor or the 
investigator decision as well as at the regulatory authorities’ request.  
In case of early study site closure or study termination, all filled out and unused CRFs 
and other documents (except for documentation that must be kept in the center) to be transferred 
to the Sponsor. The study materials may be disposed of at the site only with Sponsor’s 
permission.  
Principal Investigator should promptly inform investigators and regulatory authorities 
about early study or site termination specifying the reason for termination.  
12.3 Final report 
The final study report will be prepared by PI / sponsor  within 5 months after the data 
lock point. The report will be prepared whether the study in terminated early or completed as 
planned. The report is signed by Principal Investigator. 
 
13 ETHICAL AND REGULATORY ASPECTS 
13.1 Ethics committee 
Prior to the study initiation, the protocol and related documents (including CRFs and 
patient information materials) must receive approval by Independent Ethics Committees in 
writing. All protocol amendments also must be approved. 
The study may not be initiated in any site before the written permission from Ethics 
Committee(s) is obtained, relevant local legislation requirements are met, and the clinical trial 
protocol is signed by all involved parties. 
51 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
13.2 Informed consent 
The investigator (or his/her authorized representative) must obtain a written consent of 
every patient to participate in the study prior to any study procedures may be performed. Before 
that, the investigator (or his/her authorized representative) should inform the patient about the 
purpose, benefits, risks and requirements of the study, and about the nature of the investigated 
products. 
The patient will be provided with information about the study (Patient information 
booklet) and the informed consent form to participate in the study, set out in plain language. A 
patient must be given enough time to ask questions about the details of the study and to make a 
decision about participation in the study. 
Two originals of Patient information booklet and informed consent form to participate 
in the study must be filled out dated and signed by the patient and the person responsible for 
obtaining the informed consent. 
If the patient is unable to read the document, an unbiased witness must be present 
during the entire period of the informed consent discussion. The patient must orally agree to 
participate in the study and also fill out, sign and date the Patient information booklet and the 
informed consent form, if she can do it. Then, the witness and the person responsible for 
obtaining the informed consent must fill out, sign and date this form as well. 
Signed Patient information booklet and informed consent form is given to the patient, 
the other two signed originals will be stored by the investigator. 
Patient information booklet and Informed consent form are a part of the protocol and 
will be submitted to the Ethics Committee for approval. If new information that may be 
important for subject's consent to participate in the study becomes available, it will be reflected 
in a new version of the Patient information booklet and Informed consent form approved by the 
Ethic Committee; the new versions of the documents must be signed and dated by patients.  
13.3 Regulatory authorities 
Before the start of the study, regulatory approval to conduct this study will be obtained 
in every participating country. List of investigators and study sites will be approved.  
13.4 Confidentiality 
All documents and information provided by the investigator to the sponsor relating to 
this study are strictly confidential. 
52 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
The investigator and his/her staff take responsibility to use these data only to conduct 
the study according to the protocol. This agreement remains in force until the confidential 
information is disclosed by the sponsor. Work study protocol provided to the investigator may be 
used by the investigator or his/her staff to obtain patient’s informed consent to participate in the 
study. The content of the protocol may not be disclosed to others without written permission 
form the sponsor. 
The investigator must fill out and keep a patient screening log and an identification list 
of all enrolled patients; the investigator should content to grant access to the site for auditors 
and/or regulatory authorities representatives. Handling of the information will meet the 
requirements of professional secrecy. Patient screening log should be filled out every time the 
investigator evaluates a patient for possible enrollment to the study (by evaluating patient history 
during a visit or assessing patient medical records). 
The investigator and Sponsor must ensure the protection of personal data of study 
subjects according to applicable local regulations. Required personal data of study subjects (eg, 
socio-demographic characteristics) will be collected solely for the purposes of the study with 
minimal required details. CRFs will not contain patient names, addresses, or numbers of medical 
records/charts. No documents identifying the patients will be disclosed. Sponsor and CRO will 
not be provided with patients’ first or last names. If a patient’s name is mentioned in any 
document, the patient’s name must be deleted from the document before transferring it to 
Sponsor.  
Prior to enrollment in the study, patients will be familiarized with conditions of 
confidentiality and their personal data use, including requirement to access the data by CRAs and 
other authorized persons (in the case of audit, inspection, etc.). These conditions will be reflected 
in the Patient information booklet. The patient is enrolled into the program only after reading the 
above information and signing the Informed consent form.  
14 PATIENT INSURANCE 
Sponsor provides life and health insurance of patients participating in this study. 
15 PUBLICATIONS  
The study sponsor assumes full responsibility arising from this function, and retains 
exclusive ownership of all the results obtained in the present study, which it can use at its own 
discretion. Publication of study results is prohibited without the Sponsor permission. Results 
53 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
will be published in a peer-reviewed journal following ICJME guidelines with following 
publication in Russian language The final study report and a resulting publication will be 
provided to Abbott  upon their approval/availability. Prior to any publishing, Abbott approval of 
the study report and the manuscript(s) for publication is required and will be ensured.  
Publication of study results is subject to ethical principles. The publication authors must 
guarantee accuracy of the data, regardless of whether the data are positive or negative.  
On the part of the Sponsor, every effort will be made to publish the results of the study; 
the Sponsor ensures that the data will be provided in a reliable and clear way.  
 
 
54 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
16 REFERENCES: 
1. 
Nilsson PM, Boutouyrie P, Laurent S. Vascular aging: A tale of EVA and ADAM 
in cardiovascular risk assessment and prevention (Brief Review). Hypertension 2009; 54:3–10. 
2. 
Nilsson PM. Early vascular aging (EVA): consequences and prevention. Vasc 
Health Risk Manag 2008; 4:547–552. 
3. 
Nilsson PM, Lurbe E, Laurent S. The early life origins of vascular ageing and 
cardiovascular risk: the EVA syndrome (review). J Hypertens 2008; 26:1049–1057 
4. 
Mitchell GF, Guo CY, Benjamin EJ, Larson MG, Keyes MJ, Vita JA et al. Cross-
sectional correlates of increased aortic stiffness in the community: the Framingham Heart Study 
5. 
Sanders JL, Fitzpatrick AL, Boudreau RM, et al. Leukocyte telomere length is 
associated with noninvasively measured agerelated disease: the Cardiovascular Health Study. J  
Gerontol A Biol Sci Med Sci 2012;67:409–16 
6. 
Wong JM, Collins K. Telomeres maintenance and disease. Lancet 1994; 362:983–
988 
7. 
Gardner JP, Li S, Srinivasan SR, Chen W, Kimura M, Lu X, Berenson GS, Aviv 
A. Rise in insulin resistance is associated with escalated telomere attrition. Circulation 2005; 
111: 2171–2177 
8. 
Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic 
pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: An 
integrated index of vascular function? Circulation 2002; 106: 2085–90. 
9. 
Rupp H., Eisele B., Ziegler D. et al. United States Patent. Method for the 
treatment of diseases requiring inhibition or reduction in the activity of pH value-regulating 
bicarbonate transporter proteins. US 7.309.706.B2. Dec 18, 2007 
10. 
Tanko L.B., Christiansen C., Cox D.A., et al. Relationship between osteoporosis 
and cardiovascular disease in postmenopausal women. J Bone Miner Res 2005; 20: 1912–1920. 
11. 
Kim-Thanh Onga, Samuel Delermed, Bruno Pannierb, Michel Safarc F, Athanase 
Benetosg, Ste´phane Laurenta, and Pierre Boutouyriea. Aortic stiffness is reduced beyond blood 
pressure lowering by short-term and long-term antihypertensive treatment: a meta-analysis of 
individual data in 294 patients. Journal of Hypertension 2011, 29:1034–1042 
12. 
Riggs B.I., Melton L.J. The worldwide problem of osteoporosis: insight affirmed 
by epidemiology. Bone 1995; 17:505–11 
13. 
Hofbauer L., Shoppet M. (2001) Osteoprotegerin: a link between osteoporosis and 
arterial calcification? The Lancet. Vol.358. 
55 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
14. 
Abedin M., Tintut Y., Demer L. (2004) Vascular calcification: mechanisms and 
clinical ramifications. Aterosclerosis, thrombosis, and vascular biology; 24; 1164-1170. 
15. 
Bekker P.J., Holloway D., Nalanishi A., et.al. (1999) Osteoprotegerin (OPG) has 
potent and sustained anti-resorptive activity in postmenopausal women. J. Bone Mineral 
Reseach; 14 (Suppl.1):S180. 
16. 
Skripnikova I.A., Sobchenko K.E., Kosmatova O.V., Nebieridze D.V.  Effect of 
cardiovascular drugs on bone tissue and the possibility of their use for the prevention of 
osteoporosis. Rational Pharmacotherapy in Cardiology 2012; 8 (4): 587-94. (In Russian).  
17. 
ɊɟɤɨɦɟɧɞɚɰɢɢɩɨɥɟɱɟɧɢɸɚɪɬɟɪɢɚɥɶɧɨɣɝɢɩɟɪɬɨɧɢɢESH/ESC 2013 
 
 
56 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
17 APPENDICES 
17.1 Appendix 1 Blood pressure and heart rate measurement  
Systolic and diastolic blood pressure and heart rate will be measured at every visit 
according to ESH/ESC recommendations [17]. Blood pressure and heart rate is measured on 
patient’s arms.  
 
Position of the patient:  
Sitting in a comfortable position; the arm is on the table, at the heart level; 
sphygmomanometer cuff is placed around the upper arm, the cuff lower end should be 2 cm 
above the elbow.  
 
Blood pressure measurement conditions: 
x 
coffee and strong tea should be avoided within 1 hour prior to the measurement;  
x 
it is recommended to avoid smoking for 30 minutes before the measurement;  
x 
sympathomimetics, including nasal and eye drops, are withheld;  
x 
Blood pressure is measured after 5 minutes of resting; if the BP measurement 
procedure was preceded by significant physical or emotional stress, the resting period should be 
extended to 15-30 minutes.  
 
Equipment: 
x 
the cuff size should match the size of patient’s arm: inflatable rubber portion of 
the cuff should cover at least 80% of the arm circumference; 12-13 cm wide and 30-35 cm long 
cuff is used for adults (medium size); large and small cuffs for thick and thin arms should be 
available, respectively;  
x 
before the measurement, sphygmomanometer pointer should point at zero.  
 
Number of measurement: 
x 
at least two measurements at an interval of at least 1 minute should be made 
to evaluate BP; at the screening and enrollment visits, BP should be measured 3 times at an 
interval of at least 1 minute.  
x 
if the difference between measurements is >5 mmHg, an extra measurement is 
done; an average of the last two measurements is documented;  
57 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
 
Measurement technique:  
x 
rapidly inflate the cuff to pressure 20 mmHg higher than SBP (disappearance of 
the pulse);  
x 
BP is measured with 2 mmHg accuracy;  
x 
the cuff pressure should be reduced at a rate of about 2 mmHg per second;  
x 
the pressure at which first tone is heard corresponds to SBP (first Korotkoff 
sound);  
x 
the pressure at which the tones are no longer heard (fifth Korotkoff sound) 
corresponds to DBP. If the 5th sound cannot be determined, one should try to identify 4the 
Korotkoff sound which is characterized by a significant weakening of the tones;  
x 
if the tones are very weak, the patient should raise her arm and make a fist a few 
times, then the measurement should be repeated; the stethoscope membrane should not compress 
the artery too hard;  
x 
at the initial patient’s physical examination (at screening), blood pressure should 
be measured on both arms; later the measurements are done on the arm with the higher pressure;  
x 
heart rate is calculated based on radial pulse (counted for at least 30 seconds) after 
the last blood pressure measurement in the sitting position.  
58 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
17.2 Appendix 2 Classifications of hypertension and heart failure severity  
 
1. Hypertension severity according to ESH/ESC recommendations: 
BP categories  
SBP 
 
DBP 
Optimal  
< 120  
and  
< 80  
Normal  
120 - 129  
and/or  
80 - 84  
High normal  
- Hypertension Grade 1  
- Hypertension Grade 2  
- Hypertension Grade 3  
130 - 139  
140 - 159  
160 - 179  
 
and/or  
and/or  
and/or  
and/or  
85 - 89  
90 - 99  
100 - 109  
 
Isolated systolic hypertension *  
 
and  
< 90  
Note: *Isolated systolic hypertension should be classified as grade 1, 2, 3 based on SBP. 
If systolic blood pressure (SBP) and diastolic blood pressure (DBP) values fall into 
different grades, the hypertension severity is estimated based on the higher grade. Most accurate 
determination of hypertension grade is possible in patients with newly diagnosed hypertension, 
and in patients not taking antihypertensive medications. 
 
 
59 
 

Protocol No. MOXOC001 
Protocol Date 19 NOV 2014 
17.3 Appendix 3 Diet recommendations 
 
According to ESH/ESC 2013 Guidelines for the management of arterial hypertension 
patients should be advised to eat  
x vegetables,  
x low-fat dairy products,  
x dietary and soluble fibre,  
x whole grains and  
x protein from plant sources,  
x reduced in saturated fat and cholesterol.  
Fresh fruits are also recommended — although with caution in overweight patients 
because their sometimes high carbohydrate content may promote weight 
gain.  
Patients with hypertension should be advised to eat fish at least twice a week and 300–
400 g/day of fruit and vegetables. Soy milk appeared to lower BP when compared with 
skimmed cows’milk.  
 
60 
 

Version dd. December 12, 2014 
Patient number: __________________________ 
 
Patient Information Sheet 
 
Title:  COMPARATIVE EFFECTS OF MOXONIDINE AND BISOPROLOL ON BONE 
METABOLISM, VASCULAR AND CELLULAR MARKERS OF AGING, BLOOD 
PRESSURE IN HYPERTENSIVE POSTMENOPAUSAL WOMEN 
Principal Investigator/Sponsor: O.N. Tkacheva, Professor, Dr.Med.Sci. 
Institution/Study site: Federal State Budgetary Institution “State Scientific and Research Center 
of Prophylactic Medicine” of the Ministry of Healthcare of the Russian Federation (FSBI 
“SSRCPM” of MoH of Russia). 
 
Dear Patient! 
You have been asked to participate in a scientific and research program conducted under 
guidance of Professor, Dr. of Medical Sciences, Olga Nikolaevna Tkacheva. 
Before you agree to participate in the program, you have to get information about goals and 
content of the program, investigational products, possible risks and benefits in order to take a 
grounded decision. Such procedure is called “informed consent”. 
This document may contain words you do not understand. Please ask the investigator doctor or a 
investigator team member to explain you meaning of such words or any information that is not 
clear for you. You may keep unsigned copy of this document and think or discuss it with your 
family members or friends before you make a final decision. 
After you read information about the conducted program and all planned procedures that you 
will have to undergo, you will be asked to sign this form to be able to participate in the program. 
Your decision about participation in this program is voluntary: it means that you are free to 
decide whether to participate in it or not. You may also freely leave the program at any time 
without explanation of reasons. If you decide not to participate in this program, you may discuss 
with the study doctor standard treatment of your disease. 
General information about the program and its objective 
In this scientific program influence of the drug product Moxonidine (Physiotens) on bone 
metabolism and vascular parameters of aging are being studied. 
It is well-known that cardiovascular diseases (CVD) associated with atherosclerosis are general 
reasons of disease incidence, invalidity and mortality in developed countries, and according to 
the WHO evaluations, they threaten to become the main reason of mortality in developing 
countries too within the next decade. One of the reasons of such dramatic growth in number of 
heart attacks, blood strokes, heart failures is constant aging of population. The more the aging 
Page 1 of 7 

Version dd. December 12, 2014 
changes in a vascular wall are expressed, the easier and quicker atherosclerosis, arterial 
hypertension and other pathologic processes develop, that in their turn accelerate aging changes. 
Postmenopause is a period in a woman’s life characterizing by acceleration of aging processes, 
increasing incidence of arterial hypertension, progressiving insulin resistance. Positive influence 
of Moxonidine on insulin resistance detected in previously conducted clinical studies allows 
viewing it as a prospective antihypertensive agent with potential influence on cellular and 
vascular aging. 
Osteoporosis is one of the frontmost problems of women’s health in line with development of 
arterial hypertension. Among all the existing forms of osteoporosis postmenopausal osteoporosis 
takes about 85%. Bone metabolism is shifted to increased resorption with aging, that leads to 
osteopenia or to osteoporosis in people with predisposition to quick bone mass loss. Bone 
strength depends on the amount of bone mass and quality of bone tissue. Results of experimental 
studies showed ability of Moxonidine to inhibit processes of bone resorption by means of 
influencing on activity of osteoclasts. It was also observed in experimental studies that 
Moxonidine may slow down bone mass loss in laboratory animals, that is a prerequisite for 
clinical examination of Moxonidine influence on bone tissue density. 
This study is a complex examination of Moxonidine influence on processes of cellular, vascular 
aging, bone metabolism. 
The drug is officially registered for use in Russia, one of registered indications is arterial 
hypertension. 
Based on information received during examination of the drug it is expected that results of the 
study will help to optimize approaches to treatment of female patients with arterial hypertension 
and concurrent osteopenia during postmenopause, and to receive additional information about 
connection between progression of bone resorption and increased stiffness of arterial wall. 
In this program it is planned to examine influence of Moxonidine compared to bisoprolol on 
bone metabolism and bone tissue density in postmenopausal women with hypertension and 
osteopenia. 
It is planned to enroll postmenopausal patients with arterial hypertension and osteopenic 
syndrome. 
114 postmenopausal patients with arterial hypertension and osteopenic syndrome will participate 
in the program. 
Enrollment in the program 
Your doctor will perform necessary medical examination to determine whether you are able to 
participate in this scientific program or not. 
Examination will include medical history review, physical examination, collection of 
information about age, gender, etc., evaluation of severity and stage of arterial hypertension in 
accordance with recommendations of ESH/ESC. 
You have to inform your doctor of all known information about your disease, including all the 
drugs you take (including administration of non-prescription drugs, herbal drugs and biologically 
Page 2 of 7 

Version dd. December 12, 2014 
active food supplements) and specify whether you participate or have participated in other 
studies. 
Your doctor will ask you questions about cardiovascular diseases and other significant 
concurrent diseases and their treatment.  
Blood samples will be collected. 
Your blood pressure, pulse, height and weight will be measured. 
The following procedures will be performed: electrocardiography, X-ray absorptiometry, 
evaluation of arterial stiffness, evaluation of subclinical atherosclerosis signs. 
Program procedures 
The program consists of screening period and treatment period. If you fully correspond to the 
program inclusion criteria and want to participate in it you will receive one of the study drugs – 
bisoprolol or Moxonidine from the doctor. If at the moment of screening visit you are already 
taking any drug for hypertension, this drug will be cancelled for 2 weeks. Dosage scheme will be 
chosen by the doctor in accordance with the specific clinical situation. 
Moxonidine will be prescribed by the doctor in accordance with the approved instruction for 
medical use and within normal clinical practice. Initial dose of Moxonidine will be 0.4 mg daily 
in the morning. Drug dose is chosen for you personally by the doctor and only the doctor will be 
able to change it upon his decision depending on the treatment effect. Daily dose of Moxonidine 
may reach 0.6 mg. 
Bisoprolol will be prescribed by the doctor in accordance with the approved instruction for 
medical use and within normal clinical practice. Initial dose of bisoprolol will amount to 5 mg 
once daily in the morning. Drug dose is chosen for you personally by the doctor and only the 
doctor will be able to change it upon his decision depending on the treatment effect. Daily dose 
of bisoprolol may reach 7.5 mg. 
Besides it will be recommended for you to take calcium and vitamin D3 supplements for 
treatment of osteopenic syndrome, you will have to take 1 tablet daily with food. 
At visit 2 that will be performed in 8 weeks since enrollment visit the doctor will perform 
general medical examination, evaluate symptoms of arterial hypertension and possible adverse 
events for the preceding period. You will receive study drugs and instructions about dosage and 
regimen of the drugs administration. Expected duration of the visit is 1.5-2 hours. 
Approximately in 14 and 28 days after enrollment visit the doctor will contact you via phone to 
ask how you feel and whether you had any changes in health since the previous visit. 
At visit 3 that will be conducted in 24 weeks after the enrollment visit the doctor will perform 
general medical examination, ask you questions about concomitant therapy and possible adverse 
events. Electrocardiography will be performed and blood samples will be collected. 
At final visit 4 that will be performed in 48 weeks after the enrollment visit the blood samples 
will be collected. Your blood pressure, pulse, height and weight will be measured. The following 
Page 3 of 7 

Version dd. December 12, 2014 
procedures will be performed: electrocardiography, X-ray absorptiometry, evaluation of arterial 
stiffness, evaluation of subclinical atherosclerosis signs. Expected duration of visits 3 and 4 is 
1.5-2 hours. 
Duration of participation 
Your participation in this scientific program will start since signing of this consent form and will 
last approximately 12 months since signing of informed consent form of the Patient Information 
Sheet. 
Termination of participation in the program 
You may stop participating in this program at any moment. Also your doctor may take a decision 
about premature termination of your participation if he considers it necessary. Termination of 
participation in the program will not influence your right to get treatment or relations with your 
study doctor. Please inform your study doctor immediately if you want to stop treatment. If you 
or your doctor decide to stop your participation in this program, you may be asked to come to a 
study termination visit for final evaluation. 
Data we collect from you 
During the program information about your health condition from your medical records, all 
received information about you during your participation in the program will be collected. Your 
personal information (full name, date of birth, gender) will be used in the form of a digital code 
for analysis of medical information and for assignment of a patient number to you. Patient 
number will also be specified on the first page of the both copies of Patient Information Sheet. 
How your data will appear 
During processing and analysis you will not be identified by your name, address, insurance 
number, etc. in any databases used outside the medical institution. If study results are published, 
they will not contain any information that may identify your personality. Information that will be 
collected about you will be taken from your medical records that are kept at the Federal State 
Budgetary Institution “State Scientific and Research Center of Prophylactic Medicine” of the 
Ministry of Healthcare of the Russian Federation (FSBI “SSRCPM” of the MoH or Russia). 
Your agreement for use of your information by the study personnel starts working after signature 
of this document and has no term of validity. If you do not provide your agreement for use and 
transfer of information about your health, you will not be able to participate in this program. 
Why we collect this data 
Results of performed treatment during your participation in the program may have scientific 
value. Scientific information received in the course of this program may be used in the program 
reports and scientific reports. But information that may identify your personality will not be 
published. 
Who will see your data 
All medical records will be kept at the premises of the scientific program conduct, at the Federal 
State Budgetary Institution “State Scientific and Research Center of Prophylactic Medicine” of 
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the Ministry of Healthcare of the Russian Federation (FSBI “SSRCPM” of the MoH or Russia) 
by the responsible doctor. 
Only your doctor will have access to your personal information and your medical records. Due to 
this your doctor has to receive your consent for use and processing of your personal data. Your 
consent for use and processing of your personal data by your doctor starts working after signing 
this document and has no term of validity. You have a right to disable use and processing of your 
personal data and medical information collected during the scientific program at any moment 
without explanation of reasons. In this case you will prematurely terminate your participation in 
this program but you will not lose any rights for alternative treatment. If you do not provide your 
consent for use and transfer of your health information you will not be able to participate in this 
program. 
Information about your health will also be available to other doctors that participate in this 
scientific program, and also to members of ethics committee and regulatory and law enforcement 
executives. 
Processing of your personal information about your health includes but is not limited to 
collection, analysis, transfer (in any form), use and storage of such information. 
Risks/benefits 
Moxonidine (Physiotens®) is a prescription drug product approved for use in the Russian 
Federation, imidazoline receptor I1 agonist, indicated at arterial hypertension. Prescription and 
dosage calculation of the drug will be performed in accordance with the approved instruction for 
use, maximum daily dose may reach 0.6 mg. 
Risks connected with administration of Physiotens® may be connected with development of its 
side effects. It is necessary to note that some adverse events registered during clinical studies 
sometimes were associated with arterial hypertension symptoms but not with treatment with 
Physiotens®. 
The most frequently registered adverse symptoms are dryness in mouth, dizziness, asthenia and 
drowsiness. Such symptoms often reduce after the first weeks of treatment. 
Less frequently the following events have been registered: faint, expressed lowering of blood 
pressure, orthostatic hypotension, bradycardia, diarrhea, nausea, vomiting, dyspepsia, skin rash, 
itching, angioneurotic edema, insomnia, nervousness, tinnitus, back pain, neck pain. 
It is necessary to be especially careful at administration of Moxonidine in patients with 
atrioventricular block I grade (risk of bradycardia development); severe coronary artery disease 
and unstable angina (experience of administration is insufficient); renal insufficiency. 
Overdose 
There are reports about several cases of overdose without lethal outcome with one-time 
administration of dose up to 19.6 mg. 
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Symptoms: headache, sedative effect, drowsiness, expressed lowering of blood pressure, 
dizziness, asthenia, bradycardia, dryness in mouth, vomiting, fatigue, epigastric pain, respiratory 
distress, impairment of consciousness. 
Besides the following events are possible: short-term blood pressure increase, tachycardia and 
hyperglycemia, as it was shown in several studies of high doses on animals. 
Unknown risks 
Although Physiotens® is registered and is used for treatment of arterial hypertension, you may 
have side effects or adverse events unknown currently, i.e. not described in approved instruction 
for medical use. Please inform your doctor immediately if you develop any problems with 
health. 
Other possible treatments 
If you decide not to participate in this program, suitable standard treatment will be prescribed to 
you. 
Expenses 
Expenses for standard treatment of your condition and routine examination procedures outside 
this program will be paid by you or your insurance company. The study drug will be provided 
free of charge and medical examinations necessary for this scientific program conduct will also 
be performed free of charge. 
Compensation 
You will not receive any monetary compensation for participation in this program. 
Insurance  
Additional insurance of patients participating in this program will be provided. 
Who may I contact with for additional information? 
If you have any questions about this program, please contact the doctor responsible for its 
conduct: Ekaterina Nailievna Dudinskaya, tel.: +7 499 553 68 91 or +7 903 191 46 90, or Diana 
Vadimovna Trofimova, tel.: +7 965 126 49 52. 
You may get additional information about your rights in the Ethics Committee: +7 499 553 68 
91. 
Contact information of the Ethics Council of the Ministry of Healthcare and Social Development 
of the Russian Federation: 3 Rakhmanovsky lane, Moscow, 127994. Tel. +7 495 438-23-88. 
Informed Consent Form 
I understand what this program suggests. I have read Patient Information Sheet. I have received 
answers to all my questions. I know that participation in this program is voluntary. I can refuse to 
participate at any time and will not lose any benefits that I could have got in other case. I 
received explanations about the character of the study, risks and benefits connected with it, other 
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possible treatments, procedures and objective of the study. By signing this form I do not lose any 
of my legal rights. 
I understand that my personality will be kept secret, and information collected during this 
program will be used for scientific purposes and in scientific publications. 
I give my consent for regulatory and law-enforcement bodies or their designated employees to 
access my medical records. 
I will be informed of all new information that becomes available to my doctor in the course of 
this program and that may influence my desire to continue my participation in it. If I want to 
inform about it my treating physician, I should inform doctor Diana Vadimovna Trofimova, tel. 
+7 965 126 49 52. 
Statement of consent: 
By signing below I confirm that I have read this Patient Information Sheet and Informed Consent 
Form, discussed all details of the program with my doctor, had a chance to ask questions and 
received satisfactory answers, and I voluntarily agree to participate in this program as specified 
in this form. 
I have received signed and dated original of Patient Information Sheet and this Informed Consent 
Form. 
 
______________________________________________________________ 
Full name of a patient, printed 
 
 
____________________________________________________________________________ 
Signature of a patient  
 
 
 
 
 
 
 
Date 
 
 
______________________________________________________________ 
Full name of a Principal Investigator / authorized Co-Investigator, printed 
 
 
____________________________________________________________________________ 
Signature of a Principal Investigator / authorized Co-Investigator  
 
Date 
 
 
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