Comparison of Customized Allogenic Versus Autogenous Bone Block Graft for Alveolar Ridge Augmentation
Phase: NA
Conditions: Alveolar Bone Loss
Sponsor: Medical University of Graz

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 1 von 31  
  
  
  
Clinical Trial Protocol in 
consideration of ISO 14155  
Comparison of customized allogenic versus autogenous 
bone block graft for alveolar ridge augmentation:  
a multicenter randomized controlled trial  
  
Sponsor  
Univ. Prof. DDr. Norbert Jakse  
Medizinische Universität Graz  
Universitätsklinik für Zahnmedizin und Mundgesundheit  
Billrothgasse 4, 8010 Graz  
  
Author  
Univ. Ass. DDr. Sarah Sommer  
Medizinische Universität Graz  
Universitätsklinik für Zahnmedizin und Mundgesundheit  
Billrothgasse 4, 8010 Graz  
  
    
Principal Investigator 1.  
Assoz. Prof. PD. DDr. Michael Payer  
Medizinische Universität Graz  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 2 von 31  
Universitätsklinik für Zahnmedizin und Mundgesundheit  
Billrothgasse 4, 8010 Graz  
  
2.  
PD Dr. med. dent. Daniel S. Thoma  
University of Zurich  
Center of Dental Medicine  
Plattenstr. 11, 8032 Zurich, Switzerland  
  
  
 

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 3 von 31  
Table of Contents  
 
  
  
Page  
List of abbreviations .................................................................................................................. 4  
Responsibilities and addresses .................................................................................................. 5  
Centers where the study will be conducted: ........................................................................... 6  
Synopsis (in an official Union language determined by the Member State concerned) ......... 
7  
1. Scientific background ............................................................................................................ 
10  
Increase in implant placement and need for bone augmentation ............................. 
10  
Bone grafting with customized allografts ....................................................................... 11  
2. Name and description of the investigational bone graft ....................................................... 
13  
3. Rationale for the structure of the clinical trial .................................................................... 
14  
4. Risks and benefits of the investigational device and the clinical trial .................................. 
14  
4.1 Risk management .......................................................................................................... 
14  
5. Aims and hypotheses of the clinical trial .............................................................................. 
14  
6. Structure of the clinical trial ................................................................................................ 
14  
6.1 General information ..................................................................................................... 
14  
6.2 Devices and reference devices ................................................................................... 
15  
6.3 Test persons ................................................................................................................... 
15  
6.4 Treatments .................................................................................................................... 
16  
7. Statistical considerations ...................................................................................................... 
20  
8. Data management ................................................................................................................. 
21  
9. Modification of the study protocol ........................................................................................ 
21  
10. Deviations from the clinical study protocol ........................................................................ 23  
11. Disposition statement for the investigational bone graft .................................................... 23  
12. Legal principles ................................................................................................................... 23  
12.1 Statement of compliance: ........................................................................................ 23  
12.2 Vote of the ethics committee .................................................................................. 23  
13. Procedure to obtain informed consent ................................................................................ 24  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 4 von 31  
14. Adverse events, adverse device effects and device defects ............................................... 25  
14.1 Definitions 
.................................................................................................................... 
25 
14.2 
Recording 
of 
adverse 
events 
.................................................................................... 25 14.3 Causality assessment 
.......................................... Fehler! Textmarke nicht definiert. 14.4 Reportable 
events ............................................... Fehler! Textmarke nicht definiert.  
14.5 Reporting obligations ................................................................................................. 26  
14.6 Pregnancy 
..................................................................................................................... 
27  
15. Premature termination or discontinuation of the trial ....................................................... 27  
15.1 Termination of the trial for a proband (drop-out) ............................................... 27  
15.2 Termination of the entire trial ................................................................................ 27  
16. Clinical Investigation Report, Publication policy, Archiving ................................................ 28  
16.1 Clinical Investigation Report .................................................................................... 28  
16.2 Publication 
................................................................................................................... 
28  
16.3 Archiving ...................................................................................................................... 28  
17. References .......................................................................................................................... 28  
List of abbreviations  
  
  
CIP  
Clinical Investigation Plan  
FPFV  
First Patient First Visit  
LPLV  
Last Patient Last Visit  
BASG  
Bundesamt für Sicherheit im  
Gesundheitswesen (Federal Agency for  
Safety in Healthcare  
AE  
Adverse Event  
SAE  
Serious Adverse Event  
IEC  
Independent Ethics Committee  
GBR  
Guided Bone Regeneration  
PROM  
Patient Reported Outcome Measures  
  
  
The clinical trial is conducted in consideration of ISO 14155 - Clinical investigation of medical  
 
devices for human subjects — Good clinical practice   
  
Responsibilities and addresses  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 5 von 31  
  
Sponsor:  
Medizinische Universität Graz, Universitätsklinik für Zahnmedizin und Mundgesundheit  
Univ. Prof. DDr. Norbert Jakse  
Billrothgasse 4, 8010 Graz 0316 
385 82921 
norbert.jakse@medunigraz.at  
  
Principal Investigator 1.  
Assoz. Prof. PD. DDr. Michael Payer  
Medizinische Universität Graz  
Universitätsklinik für Zahnmedizin und Mundgesundheit  
Billrothgasse 4, 8010 Graz 0316 
385 80659 
mi.payer@medunigraz.at  
  
2.  
PD Dr. med. dent. Daniel S. Thoma  
University of Zurich  
Center of Dental Medicine  
Plattenstr. 11, 8032 Zurich, Switzerland  
+41 43 634 42 56 daniel.thoma@zzm.uzh.ch  
Centers where the study will be 
conducted:  
1. Department of Dental Medicine and Oral Health, Division of Oral Surgery and Orthodontics, 
Medical University of Graz, Billrothgasse 4, 8010 Graz, Austria, Phone: +43316 13280  
2. Center of Dental Medicine, University of Zurich Plattenstr. 11, 8032 Zurich, Switzerland,  
Phone: +41 43 634 32 52  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 6 von 31  
Laboratory  
Univ.-Ass. Dr. scient. med. Uwe Yacine Schwarze, MSc Billrothgasse 
4,8010 Graz, Austria  
uwe.schwarze@medunigraz.at  
+43 316 385 80659  
  
Data management  
DI Irene Mischak  
Billrothgasse 4,8010 Graz, Austria  
+43 316 385 13280  
  
Dr. Georgios N. Antonoglou  
Billrothgasse 4,8010 Graz, Austria  
+44 7 385 13280  
  
PD Dr. med. dent. Spyridon N. Papageorgiou  
Plattenstr. 11, 8032 Zurich, Switzerland  
  
  
  
Monitor   
Koordinierungszentrum für Klinische Studien Medizinische Universität Graz  
Neue Stiftingtalstraße 6  
8010, Graz  
Austria  
+43 316 385 78049 kks@medunigraz.at 
This clinical investigation is partially 
financed through the acquirement 
of the Large ITI Grant.   
  
Synopsis (in an official Union language determined by the Member State concerned)  
  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 7 von 31  
Sponsor  
Medizinische Universität Graz, Universitätsklinik für Zahnmedizin 
und Mundgesundheit  
Univ. Prof. DDr. Norbert Jakse  
Billrothgasse 4, 8010 Graz  
0316 385 82921 norbert.jakse@medunigraz.at  
Name  
Comparison of customized allogenic versus autogenous bone block 
graft for alveolar ridge augmentation:  
a multicenter randomized controlled trial  
Running head  
IndiALLO  
Target population  
(or indication)  
Partially edentulous patients in need of implant therapy and 
presenting an insufficient bone volume (horizontal ridge width 
<5mm) to allow placing a standard diameter implant defect-free 
in a prosthetically ideal position will be included  
Study design  
Randomized, controlled, multi-center clinical trial  
Aims of the clinical 
trial  
Primary aim of the trial  
The aim of this study is to evaluate whether allogenic and 
autogenous bone block alveolar ridge augmentations will result in 
comparable 3-dimensional clinical augmentation, radiological 
augmentation, new bone formation and % of contact area of new 
bone to bone graft six months post-surgery.   
Secondary aims of the trial  
I. 
To assess and compare the two block grafts in terms of 
safety, biocompatibility, complications and patient reported 
outcomes (PROMs) 4 months following surgery.  
II. 
To investigate the condition (health/disease) of dental 
implants 1 year after 2nd stage surgery and yearly and up to five 
years after bone augmentation  
Outcome measures  
(endpoints) of the  
Primary outcome measure  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 8 von 31  
clinical trial   
  
- 
Clinical bone ridge width gain   
- 
Radiological bone ridge width gain  
Secondary outcome measures  
- 
Histometric and histomorphometric assessment of the 
grafted site  
- 
Intraoral ridge profile change  
- 
Complications and adverse events  
- 
Patient related outcomes  
- 
Clinician related outcomes  
Number of patients  
26  
Time schedule  
With reference to the trial  
 
  
Recruitment period:2 years  
  
Planned start (FPFV): January 2025  
 
Planned end (LPLV): August 2032  
With reference to patients  
 
  
Duration of treatment: active 
phase 10 months  
Inclusion criteria  
• 
1-4 missing teeth that need to be replaced with dental 
implants  
• 
Bone ridge width insufficient for dental implant placement; <5 
mm of width as measured in a cone beam computed 
tomography at the ideal prosthetic position  
• 
Medically healthy with no known allergies to antibiotics  
• 
Non-smoker or light smoker (< 10) or previous smoker who had 
quit for 5 years or more  
• 
Periodontal health, as confirmed by clinical examination (Full 
mouth bleeding score and full mouth plaque score < 25%) and 
at least one neighboring natural tooth to the defect site(s) • 
 
Age of 18 or above  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 9 von 31  
Exclusion criteria  
• 
All contraindications against implant treatment or 
augmentative procedures (e.g., advanced systemic diseases, 
corticosteroid medication, immunodeficiency, pregnancy, 
intention to become pregnant, breastfeeding, lack of safe 
contraception)  
• 
Treatments or diseases that may have an effect on bone 
turnover or the bone itself or non-mineralized tissue 
metabolism (e.g., bisphosphonates or local radiotherapy, 
skeletal immaturity)  
• 
Pathological fractures such as those observed in (but not 
limited to) Paget’s disease or in metastatic bone diseases  
• 
Any active malignancy or patient undergoing treatment for a 
malignancy  
 
• 
Contraindications to the class of drugs under study, e.g., known 
hypersensitivity or allergy to class of drugs or the 
investigational product  
• 
Persistent compartment syndrome or neurovascular residua of 
compartment syndrome  
Investigational bone 
graft and optional 
additives:  
Botiss maxgraft® bonebuilder   
(botiss biomaterials GmbH)  
MinerOss® A                  
  
(Alltec Dental GmbH)  
Argonaut®        
  
           (Alltec Dental GmbH)  
Treatment plan  
P (patient): partially edentulous patients in need of implant 
therapy and presenting with an alveolar ridge width < 5mm   
I (intervention): individualized allogenic bone block alveolar ridge 
augmentation  
C (comparison): autogenous bone block alveolar ridge 
augmentation  
O (outcome): alveolar bone ridge width gain 
(clinical/intraoperative)  
  
  
  
  
  
1. Scientific background  
Increase in implant placement and need for bone augmentation   
  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 10 von 31  
Over the past 20 years the treatment with dental implants has become increasingly important 
in the routine therapy of patients with tooth loss. It is evident that general dentists, 
periodontists, oral surgeons and oral maxillofacial surgeons are routinely using surgical 
techniques to augment the atrophic or residual alveolar ridges in adjunct with different 
materials 2. Interestingly, in Germany in particular, there is evidence that oral and 
maxillofacial surgeons may be keener in the use of block grafting for both single and multiple 
implant treatment compared to oral surgeons3. However, based on the previous survey, both 
specialties seem to use a broad range of materials and techniques with blocks being rather 
popular.  
One of the important factors to ensure long-term implant stability is both bone quantity and  
quality4–6. Due to trauma, pathologic- or natural processes (i.e., post-extraction) there is a 
frequent need for alveolar ridge augmentation with the use of bone grafts, other biomaterials 
and occasionally biologic agents. In the event of tooth loss, resorption of underlying bone 
appears most rapidly within the first year after the event, 40%-60% bone loss emerges within 
the first three years. In spite of the development of diameter-reduced implants and shorter 
implants, in order to enable ideal implant stability and hence, clinical success, a large number 
of patients still require alveolar ridge augmentation procedures. Bone grafts are necessary to 
promote bone regeneration, adequate primary implant fixation and osseointegration. As type 
of bone grafts are concerned there is a variety of options available: autogenous bone, 
allogenic bone, xenogeneic bone and alloplastics can be used to enhance bone quantity and 
help regenerate new bone. Currently, there is a significant amount of evidence hinting that 
autogenous bone grafts could be the gold standard due to their osteoconductive and 
osteoinductive characteristics 7. The promotion of stem cells and the contained growth factors 
make autogenous bone grafts exceptional8,9 but the ideal material which will balance the 
resorption and the complete replacement with new bone is yet to be discovered. In addition, 

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 11 von 31  
the factors regarding optimal outcome after ridge augmentation may be subject to what is the 
anatomy of the area, the objective of the augmentation and a series of patient related 
factors. Therefore, to find this balance of resorption and new bone formation a large variety 
of alternatives have been developed such as hydroxyapatite, calcium sulfate bio-ceramic  
biomaterials, deproteinized bovine bone or human-derived allogenic bone10–12.   
Bone grafting with customized allografts  
  
The use of allografts is one of the most frequently applied alternatives to the acclaimed gold 
standard12 or simply to what dentists are aware of or accustomed to10. Allografts have become 
more and more popular particularly in the United States, where about one third of all bone 
grafts used in orthopedic procedures are allogenic bone grafts13 and this trend can also be partly  
extrapolated in the oral surgery 10 although a clear consensus is lacking14,15. Allografts are not  
only easy to handle and trim during surgery but they show excellent histological results 16–18  
and  
no apparent difference in the implant failure rate and implant success14,19. Additionally, in the 
benefits of allogeneic bone blocks it may be included their unlimited supply, absence of 
morbidity for the donor site (swelling, pain) and minimal safety concerns nowadays20. A recent 
systematic review compared radiological and histological outcomes after using a GBR approach 
or simply grafting with a block allograft (no membrane) versus the use of autografts for the 
alveolar ridge augmentation until today (Antonoglou et al. unpublished). In the above review a 
total of 13 comparative studies were included. Eight studies compared allograft blocks with 
autograft blocks, 4 compared xenograft blocks with autograft blocks and 1 compared two 
different allograft blocks. Direct and indirect radiographic comparisons were possible only 
amongst non-randomized studies. Direct comparisons of xenograft with autograft showed no 

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 12 von 31  
substantial difference in height change (-0.05 mm). Radiographic area change favoured 
autograft against allograft with 9.15 mm2 less reduction during healing.  
The review concludes that radiological resorption indicates that allografts might resorb at a 
higher and xenografts at a lower rate compared to autografts. Histological comparisons between 
autograft and allograft showed possible superiority of the autograft blocks in terms of reduced 
necrotic bone tissue and residual grafted material. The studied grafts used with conventional 
techniques, however, show low complication rates and an acceptable tissue quality in the 
augmented area at the end of the healing period. One trial that compares very closely with the 
suggested research has been conducted by Thoma and co-workers at the University of Zurich.   
In this study they did not obtain histological specimens and focused on dimensional changes. 
Both xenograft and autograft increased the ridge width to a comparable extent. The shrinkage 
during the healing period did not differ substantially between the two groups. and the impact 
of hard tissue augmentation on the soft tissue contour was minimal.   
Until today, there is neither an RCT nor a multicenter study investigating the previous 
outcomes, i.e. radiological and histological, simultaneously.   
  
Today, with cone-beam computed tomography there is a possibility to visualize the alveolar 
bone defects and customize allogenic bone blocks. In addition, the use of customized 
allogenic bone blocks for bone augmentation could be a potential and convenient alternative 
to the use of blocks with standard dimensions.   
  
The objective of the present trial will be to show that these customized allogenic block grafts 
behave equally well compared to autogenic block grafts investigating clinical, radiological and 
histological, and additional patient related outcomes in a non-inferiority multicenter 
randomized controlled clinical trial.   

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 13 von 31  
The significance of this trial may be summarized in that it could suggest an affordable and 
user-friendly substitute to autogenic block grafting used in alveolar ridge augmentation 
surgery.  
2. Name and description of the investigational bone graft   
Investigational bone graft Botiss maxgraft® bonebuilder (allogenic bone block), optional 
addition of MinerOss® A (allogenic bone granules), covered with Argonaut® (porcine 
collagenbased membrane).  
Step by step – customization process  
1. Data upload  
2. Block design  
3. Design check of the 3D-planning  
4. Order of allogenic bone block   
5. Production  
Duration of administration: One-time application at augmentation surgery.  
Due to the stable trabecular structure of the cancellous bone, maxgraft® bonebuilder provides 
an ideal matrix for predictable and highly effective revascularization, rapid formation of new 
bone tissue and complete bone remodeling. Simultaneously the excellent biological 
regeneration capability of maxgraft® is supported by exceptionally good flexibility on the basis 
of natural collagen content, which will facilitate screw fixation. The processing sequence meets 
highest quality standards with regard to biomechanical properties and safety, prohibiting infect 
transmission or antigenic effects. It is storable at room temperature for 5 years. However, it 
should be used as soon as possible after delivery to provide a precise fit, enabling rapid 
revascularization and fast graft incorporation.  
  
  
3. Rationale for the structure of the clinical trial  
  
There are a lot of studies about the products and procedures. However, there is no direct 
comparison of autogenous and allogenic bone blocks regarding safety, biocompatibility, 
complications and patient reported outcomes (PROMs) 4 months following surgery.  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 14 von 31  
4. Risks and benefits of the investigational bone graft and the clinical trial  
  
Allografts are not only easy to handle and trim during surgery but they show excellent 
histological results 16–18  and no apparent difference in the implant failure rate and implant 
success14,19. Additionally, in the benefits of allogeneic bone blocks it may be included their 
unlimited supply, absence of morbidity for the donor site (swelling, pain) and minimal safety 
concerns nowadays20  
4.1 Risk management  
  
All implants and biomaterials will be applied according to the manufacturer’s recommendation. 
Patients will frequently be examined for any side effects of the treatment. Standard treatment 
solutions in the case of occurring complications will be performed as a clinical risk management.    
5. Aims and hypotheses of the clinical trial  
  
Primary objective:   
The aim of this study is to evaluate whether allogenic and autogenous bone block alveolar 
ridge augmentations will result in comparable 3-dimensional clinical augmentation, 
radiological augmentation, new bone formation and % of contact area of new bone to bone 
graft six months post-surgery.   
Secondary objectives:   
I. To assess and compare the two block grafts in terms of safety, biocompatibility, 
complications and patient reported outcomes (PROMs) 4 months following surgery.  
II. To investigate the condition (health/disease1) of dental implants 1 year after 2nd stage 
surgery and yearly and up to five years after bone augmentation.  
  
6. Structure of the clinical trial  
6.1 General information  
Study design: Randomized, controlled, multi-centre clinical trial  
Study Duration: 7 years and 10 months (94 months)  
All patients will be randomly assigned using a modified permuted block randomization 
approach in two groups using Randomizer Version 2.2.0 (www.randomizer.at).   
(a) control group: autografts  
(b) test group: customized allogenic grafts  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 15 von 31  
6.2 Bone graft and optional additives  
  
Study commercial Products:  
 
Botiss maxgraft® bonebuilder   
(botiss biomaterials GmbH)  
 
MinerOss® A                  
  
(Alltec Dental GmbH)  
 
Argonaut®        
  
           (Alltec Dental GmbH)  
  
6.3 Test persons  
Partially edentulous patients in need of implant therapy and presenting an insufficient bone 
volume (horizontal ridge width <5mm) to allow placing a standard diameter implant defect-free 
in a prosthetically ideal position will be included.   
The PICO framework for the present trial is designed as follows:  
P (patient): partially edentulous patients in need of implant therapy and presenting with an 
alveolar ridge width < 5mm   
I (intervention): individualized allogenic bone block alveolar ridge augmentation  
C (comparison): autogenous bone block alveolar ridge augmentation  
O (outcome): alveolar bone ridge width gain (clinical/intraoperative)  
  
Inclusion criteria  
Bone ridge width insufficient for dental implant placement; < 5mm of width as measured in a 
cone beam computed tomography at the ideal prosthetic position  
Medically healthy with no known allergies to antibiotics  
Non-smoker or light smoker (< 10) or previous smoker who had quit for 5 years or more  
Periodontal health, as confirmed by clinical examination (Full mouth bleeding score and full 
mouth plaque score < 25%) and at least one neighbouring natural tooth to the defect site(s)  
Age of 18 or above  
  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 16 von 31  
Exclusion criteria  
Contraindications against implant treatment or augmentative procedures (e.g., advanced 
systemic diseases, corticosteroid medication, immunodeficiency, pregnancy, intention to 
become pregnant, breastfeeding, safe contraception)  
Treatments or diseases that may influence bone turnover or the bone itself or non-mineralized 
tissue metabolism. (e.g., bisphosphonates or local radiotherapy, skeletal immaturity).  
Pathological fractures such as those observed in (but not limited to) Paget’s disease or in 
metastatic bone diseases.  
Any active malignancy or patient undergoing treatment for a malignancy   
Contraindications to the class of drugs under study, e.g., known hypersensitivity or allergy to 
class of drugs or the investigational product  
Persistent compartment syndrome or neurovascular residua of compartment syndrome.  
  
The anticipated total duration of the clinical trial is 94 months with an active phase of 10 
months. The estimated time required to obtain the stated number of persons is 24 months.   
  
6.4 Treatments  
  
Augmentation surgery  
Prior to the start of the surgery, patients will rinse with 0.2% of chlorhexidine and receive a 
perioperative antibiosis.  The area/areas intended for surgery will be carefully anaesthetized.  
Recipient site preparation: A paracrestal incision placing the line of incision towards the oral 
aspect of the ridge will be applied. Oblique releasing incisions will be used to allow for a wide 
flap basis as well as sufficient access to the defective ridge area. Any soft tissues remaining on 
the crest were meticulously removed and the ridge width will be measured. The cortical bone 
plate will be perforated at numerous locations symmetrically distributed across the area of the 
defect with a bur (round carbide bur, 1,4 mm).  
Donor site preparation (control only): Depending on the size of the ridge defect (recipient site) 
and the donor site anatomy, the blocks will be harvested from the mandibular symphysis or the 
retromolar area. A mucoperiosteal flap will be elevated at the donor site, followed by 
preparation with a fissure bur or a piezo device and careful block graft mobilization 26.  
Ridge augmentation at recipient site: In the test group, the customized allograft block:   

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 17 von 31  
Based on CT/CBCT scans of the patient, the allogenic bone block has already been virtually 
designed using 3D CAD/CAM technology prior to surgery. Manual adjustment of the block during 
the operation is rarely required. The allogenic block may be applied directly onto the defect, 
reducing the risk of infection as well as surgery time. The individual design provides a precise 
fit between local bone and the allogenic bone block, enabling fast graft incorporation and rapid 
revascularization.    
In the control group, the blocks will also be adapted to the defect site morphology. With a small 
drill, holes for fixation will be prepared and the bone blocks will be immobilized with one or 
two screws. Subsequently, a layer of bone particles will be applied if needed to cover the 
autogenous bone and to fill up voids.  
The obtained ridge width will be again measured before application of the membrane. In both 
groups, the collagen membrane will be trimmed to extend the augmented area 2-3 mm onto the 
intact bony borders of the defect. The membrane will be fixated using resorbable fixation pins. 
Tension free wound closure will be obtained through releasing incisions in the periosteum. A 
horizontal mattress suture and further single interrupted sutures will be placed intending a 
primary wound closure in both groups.  
All patients will receive analgesic and anti-inflammatory medications and will be instructed to 
rinse with chlorhexidine (Chlorhexamed FORTE alkoholfrei 0.2%). Subsequently, penicillin will 
be given for 4 consecutive days. Temporary removable partial dentures will be carefully checked 
and adapted if necessary, to avoid trauma to the surgical area.   
All patients will be asked to fill out VAS forms for the assessment of bleeding, swelling, pain and 
bruising for the following 7 days. The levels of each parameter will be marked by the patient on 
the form from 0 (e.g. no swelling) to 10 (e.g. very severe swelling). Compliance in completing 
the records of VAS and analgesic consumption forms will be monitored at the follow-up visits.  
All sutures will be removed 7 days following augmentation surgery.   
  
Implant placement and Re-entry (at 6 months post augmentation)   
Six months following ridge augmentation, re-entry surgery and implant placement will be 
performed: Before surgery a CBCT scan will be conducted. After rinsing with chlorhexidine 
(Chlorhexamed FORTE alkoholfrei 0.2%) for one minute and application of local anaesthetics, 

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 18 von 31  
flaps will be raised to visualize the augmented ridge and the ridge width will be measured by 
means of a caliper to assess the oro-facial bone width to the nearest millimeter at the 
prospective implant. A hard tissue biopsy will be obtained in the prospective implant position 
by means of a trephine bur with an inner diameter of 1.8 mm. Subsequently, implants will be 
placed according to the manufacturer’s instruction and in a prosthetically ideal position. 
Additional GBR procedures will be performed in case of dehiscence or fenestration defects at 
the implants. Flaps will then be adapted to allow a submerged healing of the implant.  
After the implant placement post-operative occlusal photographs and a CBCT scan will be taken. 
All patients will be asked to use 0.2 % chlorhexidine mouth rinse twice daily until suture removal 
7 days after implant placement.   
Furthermore, post-operative occlusal photographs will be taken.   
  
  
  
 

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 19 von 31  
Flowchart of study procedures:  
Visits  
Vi 
1 
Sc 
en 
g  
sit  
re 
in 
Visit 2  
Augme 
ntation 
 Visit 
3 
Sut 
ure 
rem 
oval  
Visit 4 
Implant 
ation  
Visit 
5 
Sut 
ure 
rem 
oval  
Visit 6  
2nd 
stage 
surgery 
Visit  
7 
Cro 
wn 
inse 
rtion  
Visi t 
8 Foll 
owup  
  
Visi t 
9 Foll 
owup  
  
Visi t 
10 
Foll 
owup  
  
Visi t 
11 
Foll 
owup  
  
Visi t 
12 
Foll 
owup  
  
Day/mont 
hs/years  
 
0  
+7 
day 
s  
+6 
months 
= 180 
days past 
augme 
ntation 
+6  
mo 
nths 
and  
7  
day 
s  
+10 
months 
=300 
days 
past  
augme 
ntation 
=120 
days 
past  
implant 
ation  
2-4  
wee 
ks  
after  
2nd 
stag 
e  
surg 
ery  
1  
yea r  
afte r  
2nd 
sta ge  
sur 
ger y  
2  
yea rs  
afte r  
2nd 
sta ge  
sur 
ger y  
3  
yea rs  
afte r  
2nd 
sta ge  
sur 
ger y  
4  
yea 
rs afte 
r  
2nd 
sta ge 
sur 
ger 
y  
5  
yea rs  
afte r  
2nd 
sta ge  
sur 
ger y  
Informed 
consent  
X  
  
  
  
  
  
  
  
  
  
  
  
Demogra 
phics  
X  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history  
X  
  
  
  
  
  
  
  
  
  
  
  
In/Exclusi 
on criteria 
X  
  
  
  
  
  
  
  
  
  
  
  
Pregnanc 
y test  
X  
X  
  
X  
  
  
  
X  
X  
X  
X  
X  
Photogra 
phs  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Impressio 
n  
X  
  
X  
  
X  
  
X  
X  
  
X  
  
X  
Clinical  
examinati 
on  
X  
  
  
  
  
  
  
X  
X  
X  
X  
X  
Randomiz 
ation  
X  
  
  
  
  
  
  
  
  
  
  
  
Cone  
Beam CT  
X  
nach 
  
Vor  
  
  
  
X  
X  
X  
X  
X  
Augme 
Implant 
ntation 
atio n  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 20 von 31  
X  
X  
  
nach  
Implant 
atio n  
X   
OPG  
X  
  
  
  
  
  
  
  
  
  
  
  
Augment 
ation 
surgery  
  
X  
  
  
  
  
  
  
  
  
  
  
Administe r 
study  
medicatio 
n  
  
X  
  
X  
  
  
  
  
  
  
  
  
Suture 
removal  
  
  
X  
  
X  
  
  
  
  
  
  
  
Implant  
placemen 
t  
  
  
  
X  
  
  
  
  
  
  
  
  
Adverse 
events/st 
udy 
specific 
adverse 
events  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
PROMs  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
7. Statistical considerations  
  
The sample size calculation was performed with nQuery 8   
When the sample size in each group is 13, a two group one-sided 0.025 significance level t-test 
will have 80% power to reject the null hypothesis that the test group (allogenic bone blocks) 
and standard (augogenous bone blocks) are not non-inferior (the difference in means, μT-μS, is 
3.0 or farther from zero in the same direction) in favor of the alternative hypothesis that the 
means of the two groups are non-inferior, assuming that the expected difference in means is 
0.63 and the common standard deviation is 2.0.  
  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 21 von 31  
The primary endpoint in the initial trial will be sufficient intraoperative bone ridge width.   
  
  
  
8. Data management  
The inquiry, circulation and storage of personal data will be accomplished according to the 
data privacy act  
After termination of the study all documents will be stored in the archive of the Department 
of Dental Medicine and Oral Health for 15 years.  
The data will be captured into Excel (Microsoft Corporation, Redmond, Washington, USA). 
Mean, standard deviations (SD), medians, quartiles and min/max will be derived for 
continuous variables and counts for categorical data. Intergroup comparisons will be tested by 
a two-sided Wilcoxon–Mann–Whitney test because of the small sample size, and the 
nonnormality of the data and intra-group comparisons will be performed with Wilcoxon-signed 
rank test for continuous variables. All categorical variables will be tested with Chi-squared 
tests or Fisher’s exact test.   
The primary endpoint will be the clinically evaluated ridge width. To allow commenting on the 
possible equivalence of the two groups, the 90% confidence intervals will be provided in 
addition. The significance level will be set at 5%. No correction for the multiple testing for the 
secondary endpoints will be applied. We will perform sensitivity analyses to include centre 
and defect dimensions effects, dimensions of keratinized mucosa and different methods for 
handling missing data. R (version 2.15.0) will be used for all statistical analyses.   
Additionally, regarding outcomes which will be collected repeatedly in time such as 
peri/implant clinical measurement a general linear model (GLM) for repeated measures will 
be used and evaluate the effect of test and control treatment on them.   
This trial will be registered with the European platform for trial registration 
(https://www.clinicaltrialsregister.eu).  
  
9. Modification of the study protocol  
  
The vote of the ethics committee applies solely to the information contained in the application; 
it does not include substantial extensions or modifications of the research project undertaken 

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 22 von 31  
at a later point in time. In case of any substantial modification, an amendment of the study 
protocol signed by the Principal Investigator is required. Any modification of the study protocol 
must be attached, as an amendment, to all study protocols in circulation. The ethics committee 
must be informed of all substantial modifications in the study protocol. In case of modifications 
in the study protocol that are not merely of a formal nature but contain changes pertinent to 
the study participants, a renewed vote of the ethics committee must be obtained. If applicable, 
the patients/probands must be informed in the patient information and consent form about 
changes in the terms and conditions of the trial.   
  
  
 

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 23 von 31  
10. Deviations from the clinical study protocol  
If there is a deviation from the CIP, the deviations have to be recorded and analysed in order 
to prevent further deviations.  
  
11. Disposition statement for the investigational bone graft  
  
Access to the investigational bone graft should be controlled. The investigational bone graft 
should only be used in the clinical trial and in accordance with the CIP.  
The sponsor must preserve all records that document the material site of all investigational bone 
graft from a consignment of investigational bone graft to the study sites until they are returned 
or disposed.  
The Principal Investigator or an authorised representative must preserve records that document 
the receipt, usage, return, and disposal of the investigational bone graft; the records must 
contain the following:  
Estimated date of receipt: 01/2024  
  
a) Identification of each investigational bone graft (batch number/serial number or 
distinct code); Not available yet  
b) Date of expiry if applicable; Not available yet  
c) Date of use; Not available yet  
  
d) Identity of the test person; Not available yet  
  
  
12. Legal principles  
  
12.1 Statement of compliance:  
During the implementation of the trial, the (current versions of) following guidelines and laws 
must be followed in addition to the Declaration of Helsinki (such as):  
  
•   
• 
Medical University of Graz Guideline on Standards for Good Scientific Practice   
• 
Applicable aspects of ISO 14155  
• 
Austrian Act on Tissue safety (Gewebesicherheitsgesetz)  
  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 24 von 31  
12.2 Vote of the ethics committee  
  
The clinical trial may be started only after the competent ethics committee has issued its 
statement of approval.  
  
13. Procedure to obtain informed consent  
  
The investigator must explain to each subject the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits and any discomfort 
it may entail. Each subject must be informed that the participation in the study is voluntary and 
that he/she may withdraw from the study at any time and that withdrawal of consent will not 
affect his/her subsequent medical treatment. The subject must be informed that his/her 
medical records may be examined by authorized individuals other than their treating dentist. 
All subjects for this study will be provided a subject information sheet and a consent form 
describing this study and providing sufficient information for subjects to make an informed 
decision about their participation in this study.   
The subject information sheet and the consent form will be submitted with the protocol for 
review and approval by the Independent Ethics Committee (IEC) for the study. The formal 
consent of a subject, using the IEC-approved consent form, must be obtained before that subject 
is submitted to any study procedure. Prior to subject participation in the study, informed consent 
will be obtained from each subject. The subject should read and consider the statement before 
signing and dating it and should be given a copy of the signed document. The consent form must 
also be signed and dated by the investigator (or his designee) and it will be retained as part of 
the study records.  
Informed consent will be obtained after description and discussion of the procedures.  
Standardized informed consent forms will be used additionally.   
  
  
14. Adverse events  
  
14.1 Definitions  
  
Adverse Event (AE) is defined as any untoward medical occurrence, unintended disease or 
injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users 

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 25 von 31  
or other persons, in the context of a clinical investigation, whether or not related to the clinical 
trial.  
Swelling, bleeding, bruising, general allergic reaction, local allergic reaction, paresthesia, 
sequestrum, fracture of the jaw, loss of graft, implant loss  
  
An Adverse Reaction is an AE where a causal relationship to the study devices or study 
procedures is assumed.  
  
Serious Adverse Event (SAE) is defined as any adverse event that led to any of the following: 
a) death,  
b) serious deterioration in the health of the subject, that resulted in any of the following:  
i. life-threatening illness or injury, ii. permanent impairment of 
a body structure or a body function, iii. hospitalisation or 
prolongation of patient hospitalisation,  
iv. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function,  
v. chronic disease,  
c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect  
  
A Serious Adverse Reaction (SAR) is a SAE where a causal relationship to the study devices or 
the study procedures is assumed.  
  
14.2 Recording of adverse events  
  
The sponsor shall fully record all of the following:   
(a) any adverse event of a type identified in the clinical investigation plan as being 
critical to the evaluation of the results of that clinical investigation;   
(b) any serious adverse event;   
(c) any new findings in relation to any event referred to in points (a) to (b).  
  
List of adverse events as being critical to the evaluation of the results of the clinical 
investgation:   
Loss of graft  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 26 von 31  
  
  
14.5 Reporting obligations  
  
Report by the investigator to the sponsor  
The sponsor shall be informed by the investigator immediately, but not later than 3 calendar 
days after investigation site study personnel’s awareness of the event.  
  
Report by the sponsor to the ethics committee  
Reportable events that occurred within the domestic territory (Austria) have to be reported to 
the concerned ethics committee by the sponsor.  
  
  
14.6 Pregnancy  
  
A pregnancy test in study subjects of childbearing potential is mandatory at screening and 
before radiographic and invasive clinical procedures. In case of pregnancy the study subject 
will be excluded from the trial.   
  
15. Premature termination or discontinuation of the trial  
  
In case of multiple graft losses and cases of incompatibility or symptoms of graft 
incompatibility premature termination and unlocking of blinded data will be performed. 
Further sequence patients will be provided with an alternative treatment plan and enrolled in 
regular follow up and maintenance programs.   
  
15.1 Termination of the trial for a proband (drop-out)  
  
One or several of the following circumstances may lead to the termination of the trial for a 
single proband (this proband shall be counted as a drop-out):  
• The proband's withdrawal of his/her consent  
• Intolerable adverse effects  
• Violation of the study protocol  
• Occurrence of an exclusion criterion  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 27 von 31  
• Occurrence of a disease  
• Pregnancy  
• Other circumstances that would endanger the health of the proband if he/she were to 
continue his/her participation in the trial.  
  
15.2 Termination of the entire trial  
  
For the benefit of, and in the interest of the probands, the Principal Investigator is authorised 
to terminate the trial prematurely at any time when serious adverse effects or other 
unforeseeable circumstances occur.  
  
16. Clinical Investigation Report, Publication policy, Archiving  
  
16.1 Clinical Investigation Report  
  
The Clinical Investigation report will be provided to the concerned regulatory 
authorities/ethics committee/s until one year after termination of the clinical investigation.  
  
16.2 Publication   
  
Data will be collected, analysed and incorporated in a manuscript for publication in a highly 
ranked Pubmed listed scientific journal.   
  
16.3 Archiving  
  
The medical records of the study participants must be kept by the hospital for at least 30 
years, by outpatient clinic for at least 10 years (§ 10 Para. 1 No. 3 KAKuG, § 17 Para. 2 KAG).  
  
17. References  
  
1. 
Berglundh, T. et al. Peri-implant diseases and conditions: Consensus report of 
workgroup 4 of the 2017 World Workshop on the Classification of Periodontal 
and Peri-Implant Diseases and Conditions. J. Periodontol. 89, S313–S318 (2018).  
  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 28 von 31  
2. 
Aghaloo, T., Misch, C., Lin, G.-H., Iacono, V. & Wang, H.-L. Bone Augmentation 
of the Edentulous Maxilla for Implant Placement: A Systematic Review. Int. J. 
Oral Maxillofac. Implants 31, s19–s30 (2017).  
  
  
3. 
Korsch, M. et al. Pre-implantological treatment routines for alveolar ridge 
atrophy - An investigation among maxillofacial and oral surgeons in southern 
Germany. BMC Oral Health 20, 195 (2020).  
  
4. 
Clark, D. & Levin, L. Dental implant management and maintenance: How to 
improve long-term implant success? Quintessence Int. 47, 417–23 (2016).  
  
  
5. 
Wang, Y., Zhang, Y. & Miron, R. J. Health, Maintenance, and Recovery of Soft 
Tissues around Implants. Clinical Implant Dentistry and Related Research vol. 18 
618–634 (2016).  
  
6. 
Daubert, D. M., Weinstein, B. F., Bordin, S., Leroux, B. G. & Flemmig, T. F.  
Prevalence and Predictive Factors for Peri-Implant Disease and Implant Failure: 
A Cross-Sectional Analysis. J. Periodontol. 86, 337–347 (2015).  
  
  
7. 
Sakkas, A., Wilde, F., Heufelder, M., Winter, K. & Schramm, A. Autogenous bone 
grafts in oral implantology—is it still a “gold standard”? A consecutive review of 
279 patients with 456 clinical procedures. Int. J. Implant Dent. 3, (2017).  
  
8. 
Whitt, J. et al. Efficacy of stem cell allograft in maxillary sinus bone 
regeneration: a randomized controlled clinical and blinded histomorphometric 
study. Int. J. Implant Dent. 6, (2020).  
  
  
9. 
Galindo-Moreno, P. et al. Histopathological comparison of healing after 
maxillary sinus augmentation using xenograft mixed with autogenous bone 
versus allograft mixed with autogenous bone. Clin. Oral Implants Res. 29, 192– 
201 (2018).  
  
10. 
Haugen, H. J., Lyngstadaas, S. P., Rossi, F. & Perale, G. Bone grafts: which is the 
ideal biomaterial? J. Clin. Periodontol. 46, 92–102 (2019).  
  
  
11. 
Kloss, F., … V. O.-C. oral implants & 2018,  undefined. Comparison of allogeneic 
and autogenous bone grafts for augmentation of alveolar ridge defects—A 12-
month retrospective radiographic evaluation. Wiley Online Libr. 29, 1163–1175 
(2018).  
12. 
Sakkas, A., Wilde, F., Heufelder, M., Winter, K. & Schramm, A. Autogenous bone 
grafts in oral implantology—is it still a “gold standard”? A consecutive review of  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
  
Page 29 von 31  
279 patients with 456 clinical procedures. Int. J. Implant Dent. 3, 23 (2017).  
  
13. 
Molenaars, R. J., Schoolmeesters, B. J. A., Viveen, J., The, B. & Eygendaal, D. 
There is a role for allografts in reconstructive surgery of the elbow and 
forearm. Knee Surgery, Sports Traumatology, Arthroscopy vol. 27 1840–1846 
(2019).  
  
14. 
Liang, F. et al. Alternatives to Autologous Bone Graft in Alveolar Cleft 
Reconstruction. J. Craniofac. Surg. 29, 584–593 (2018).  
  
15. 
Alyahya, A. & Swennen, G. R. J. Bone grafting in orthognathic surgery: a 
systematic review. International Journal of Oral and Maxillofacial Surgery vol. 
48 322– 331 (2019).  
  
16. 
Rtinkey. Alveolar Ridge and Sinus Augmentation Utilizing Platelet&#x2010;Rich  
Plasma in Combination With Freeze&#x2010;Dried Bone Allograft: Case Series; Alveolar  
Ridge and Sinus Augmentation Utilizing Platelet&#x2010;Rich Plasma in Combination 
With Freeze&#x2010;Dried Bone Allograft: Case Series. Wiley Online Library vol. 71 
https://aap.onlinelibrary.wiley.com/doi/abs/10.1902/jop.2000.71.10.1654?casa_token 
=FHz1_PeQqi8AAAAA:FD0OOSj61a_aUT0BE2HWrGKcgL_3BR2OALsoim0EIS1hEtk4AaMGlLp
mzwTjRPTmdLrIIoLryyR067s (2000).  
  
17. 
Geurs, N. C. et al. Clinical and Histologic Assessment of Lateral Alveolar Ridge 
Augmentation Using a Synthetic Long-Term Bioabsorbable Membrane and an 
Allograft. J. Periodontol. 79, 1133–1140 (2008).  
  
18. 
Sterio, T., Katancik, J., … S. B.-… of P. & & 2013,  undefined. A prospective, 
multicenter study of bovine pericardium membrane with cancellous particulate 
allograft for localized alveolar ridge augmentation. search.ebscohost.com.  
  
19. 
Nissan, J. et al. Age-related new bone formation following the use of cancellous 
bone-block allografts for reconstruction of atrophic alveolar ridges. Clin. 
Implant Dent. Relat. Res. 20, 4–8 (2018).  
  
20. 
Grassi, F. R. et al. Design Techniques to Optimize the Scaffold Performance: 
Freeze-dried Bone Custom-made Allografts for Maxillary Alveolar Horizontal 
Ridge Augmentation. Materials (Basel). 13, 1393 (2020).  
  
21. 
Mühlemann, S., Lakha, T., Jung, R. E., Hämmerle, C. H. F. & Benic, G. I. 
Prosthetic outcomes and clinical performance of CAD-CAM monolithic zirconia 
versus porcelain-fused-to-metal implant crowns in the molar region: 1-year 
results of a RCT. Clin. Oral Implants Res. 31, 856–864 (2020).  
  

 
Study protocol: IndiALLO  
  
   
  
  
  
Version 4/19.03.2025   
  
Page 30 von 31  
22. 
Pohl, V. et al. Short dental implants (6 mm) versus long dental implants (11–15 
mm) in combination with sinus floor elevation procedures: 3-year results from a 
multicentre. J Clin Periodontol 44, 438–445 (2017).  
23. 
Sailer, I. et al. 10-year randomized trial (RCT) of zirconia-ceramic and 
metalceramic fixed dental prostheses. J. Dent. 76, 32–39 (2018).  
  
24. 
Payer Vincent Arnetzl Robert Kirmeier Martin Koller Gerwin Arnetzl Norbert 
Jakse, M. et al. Immediate provisional restoration of single-piece zirconia 
implants: a pro-spective case series-results after 24 months of clinical function. 
Wiley Online Libr. 24, 569–575 (2012).  
  
25. 
Kühl, S. et al. The influence of bone marrow aspirates and concentrates on the 
early volume stability of maxillary sinus grafts with deproteinized bovine bone 
mineral - first results of a RCT. Clin. Oral Implants Res. 25, 221–225 (2014).  
  
26. 
Von Arx, T. & Buser, D. Horizontal ridge augmentation using autogenous block 
grafts and the guided bone regeneration technique with collagen membranes: a 
clinical study with 42 patients. Wiley Online Libr. 17, 359–366 (2006).  
  
27. 
Razi, T., Emamverdizadeh, P., Nilavar, N. & Razi, S. Comparison of the 
Hounsfield Unit in CT scan with the Gray Level in cone-beam CT. J. Dent. Res. 
Dent. Clin. Dent. Prospects 13, 177–182 (2019).  
  
28. 
Bastami, F. et al. Can gray values derived from CT and cone beam CT estimate 
new bone formation? An in vivo study. Oral Maxillofac. Surg. 22, 13–20 (2018).  
29. 
Edwards, P. Questionnaires in clinical trials: Guidelines for optimal design and 
administration. Trials vol. 11 2 (2010).  
  
30. 
McGrath, C., Comfort, M. B., Lo, E. C. M. & Luo, Y. Patient-centred outcome 
measures in oral surgery: Validity and sensitivity. Br. J. Oral Maxillofac. Surg. 
41, 43–47 (2003).  
  
31. 
Papapanou, P. N. & Susin, C. Periodontitis epidemiology: is periodontitis 
underrecognized, over-diagnosed, or both? Periodontology 2000 vol. 75 45–51 
(2017).  
  
32. 
Team, R. C. R: A language and environment for statistical computing. (2013).  
  
33. 
Hu, Y. & Hu, F. Balancing Treatment Allocation over Continuous Covariates: A 
New Imbalance Measure for Minimization. J. Probab. Stat. 2012, 13 (2012).