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Trial registered on ANZCTR


Registration number
ACTRN12613000345785
Ethics application status
Approved
Date submitted
24/03/2013
Date registered
2/04/2013
Date last updated
2/04/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Single Blinded Randomized Controlled Clinical Trial on the Efficacy of Ozone Therapy on Breast Cancer-Related Lymphedema
Scientific title
Efficacy of Ozone Therapy on Breast Cancer-Related Lymphedema: A Single Blinded Randomized Controlled Clinical Trial

Secondary ID [1] 282183 0
nil
Universal Trial Number (UTN)
Trial acronym
Efficacy of Ozone Therapy on Breast Cancer-Related Lymphedema
Linked study record

Health condition
Health condition(s) or problem(s) studied:
breast cancer related lymphedema 288682 0
Condition category
Condition code
Physical Medicine / Rehabilitation 289029 289029 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ozone therapy Application Using the Rectal Insufflation Method: Before starting the first treatment session, each patient in the study group was instructed carefully about the ozone therapy procedure as well as, its safety, values and effects to gain her confidence and cooperation during the treatment sessions. Furthermore, each patient was advised and instructed to evacuate her bladder and rectum before starting each ozone therapy session.
Each patient assumed a relaxed modified side lying position, then the catheter was held and lubricated with a neutral lubricant (KY gel), and closed by the clamp before inserting it into the rectum through the anus. After that, the syringe was introduced into the free end of the catheter, and the clamp was removed, and the ozone was injected into the catheter, after that, the catheter was closed with the clamp again, to change the syringe. Then each patient received ozone in form of rectal insufflations with ozone concentration of 20 µg/ml, increased gradually up to 40 µg/ml and the volume was ranged from150-300ml. Three syringes of 50 ml were filled with ozone from the portable generator (Ozomed, Kastner Praxisbedarf- D-76437 Rastatt), with total ozone dose of 150 ml, with the appropriate concentration was delivered the ozone into the rectum via the catheter in the first session, then the dose and concentration of the ozone were increased gradually in the subsequent sessions to reach the maximum range (ozone dose of 300 ml, concentration of 40 µg/ml by using 6 syringes). This procedure was repeated from three to six times according to the ozone dose which was used. Finally, the catheter was removed from the patient's rectum, when all the syringes were used. Then each patient was instructed to clean her anus by using sterile dressing and instructed to rest for 5 minutes. The procedure was repeated three times weekly for the first two months and two times for the last month (Knoch, Roschke, & Klug, 1987; Carpendale, Freeberg, Meleod, 1993; Bocci, Borrelli ,Corradeschi, & Valacchi, 2000).
The total duration of intervention was 3-month.

"In additional to the Ozone therapy, patients were also advised to perform daily limb exercises which included (1) Arm elevation to 180 degrees with elbows straight (2) Internal rotation with the hand on the back trying to reach as high as possible (3) Abduction with the fingertips on the shoulders (4) Elbows together and apart with the hands behind the neck. Patients were also required to do the following exercises in the standing position: (1) Arm extension with a stick held horizontally behind the back (2) Shoulders forward, backwards, upwards, and downwards (3) Shoulder circles with the fingertips on the shoulder (4) Arm elevation standing in a corner with the back of the hand gliding along the wall. Patients were told to perform each exercise five times in every set on a daily basis. Patients were also instructed to in the skin care to maintain the affected area clean and dry to decrease the risk of infection. All women were instructed to wear pressure garment that provides pressure of (40 to 60 mmHg), and for 20 h daily during the period of the study as reported. All patients were given a diary logbook to complete on a daily basis during the intervention period. They were asked to maintain a daily self-report of their daily exercise activities and duration of wearing garment. The total duration of the intervention was 3 months.".
Intervention code [1] 286778 0
Treatment: Other
Intervention code [2] 286779 0
Rehabilitation
Comparator / control treatment
All patients were given advice to perform daily limb exercise program (Omar, Ebid, & El Morsy, 2011). Participants were instructed in the skin care to maintain the affected area clean and dry to decrease the risk of infection. All women were instructed to wear pressure garment that provides pressure of (40 to 60 mmHg), and for 20 h daily during the period of the study as reported (Omar, Ebid, & El Morsy, 2011). All patients were given a diary logbook to complete on a daily basis during the trial period. They were asked to maintain a daily self-report of their daily exercise activities and duration of wearing garment. The content of the logbooks did not differ between ozone group and control groups

All patients were given advice to perform daily limb exercise program
including the following:
(1) Arm elevation to 180 degrees with elbows straight
(2) Internal rotation with the hand on the back trying to reach as
high as possible
(3) Abduction with the fingertips on the shoulders
(4) Elbows together and apart with the hands behind the neck
And the following exercises in the standing position:
(1) Arm extension with a stick held horizontally behind the back
(2) Shoulders forward, backwards, upwards, and downwards
(3) Shoulder circles with the fingertips on the shoulder
(4) Arm elevation standing in a corner with the back of the hand
gliding along the wall.
Patients were told to perform each exercise five times in every set, daily for 3-month.

Control group
Active

Outcomes
Primary outcome [1] 289144 0
An absolute change in limb circumference and volume
Circumference and water-displacement volumetric measurements were used to quantify limb size at each evaluation. Each limb was immersed in a water-filled tank, and the displaced fluid was collected and measured to the nearest milliliters. Circumference was measured every 3 cm beginning at the ulnar styloid process and continuing 45 cm proximally, as well as at the metacarpals and mid-hand. Arm volume was then calculated based on the formula for a truncated cone. Each measurement was repeated three times, and the average has been calculated. The correlation between the calculated volume from circumference and total water displacement volume were high (r=0.99) for both surgical and contralateral upper extremities (Karges, 1996; Karges, Mark, Stikeleather, & Worrell, 2003; Sander, Hajer, Hemenway, & Miller, 2002).

Where V is the volume of the segment, C1 and C2 are the circumferences at the ends of the segment, and h is the distance between them (segment length), p =3.1416.
The lymphedema volume was determined by comparing the difference in the arm volume between the affected and unaffected arms. Thus, each subject's unaffected arm served as a control. The changes in lymphedema volume were expressed in both milliliters and percentage reduction. The percentage reduction was calculated as follows:
Differences initial - Differences at each point of assessment x100
Difference initial
Where difference=affected arm volume-unaffected arm volume.
Timepoint [1] 289144 0
Evaluated at the baseline (0wK) and after the end of 12 weeks of intervention (12wk).
Secondary outcome [1] 301923 0
Ultrasound imaging was obtained by the blinded radiologist as the secondary outcome measurement. ultrasound imaging was taken to measure;
1-Skin thickness was determined by measuring the distance between the entry echo and the dermis/subcutis boundary.

2-Subcutis thickness was set between the bottom of the dermis, and the line generated by the fascial connective tissue sheet overlying the muscle
Timepoint [1] 301923 0
Evaluated at the baseline (0wK) and after the end of 12 weeks of intervention (12wk).

Eligibility
Key inclusion criteria
All patients had been undergoing breast cancer surgeries. Subjects who fulfilled the following criteria were eligible for enrollment in the study; (1) unilateral BCRL, (2) mild to moderate lymphedema defined as circumferential difference of 2-8 cm across 3 sites (Omar, Ebid, & El Morsy, 2011), and /or a volume difference of 200-750ml between the upper limbs ( Carati, Anderson, Gannon, & Piller, 2003; Lau & Cheing, 2009), ;Piller, 2000; Piller & O’Connor, 2002; Petrek, Senie, Peters, & Rosen, 2001), (Wilke, McCall, & Posther, 2006).
Minimum age
45 Years
Maximum age
65 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients were excluded if they had (1) local recurrent or distant metastases, cellulites, chronic inflammatory diseases, (2) medication that influences body fluid and electrolyte balance, (4) history of physical therapy other than skin care, and bandaging directed to lymphedema within the previous six months (Omar, Ebid, & El Morsy, 2011; Carati, Anderson, Gannon, & Piller, 2003; Teas, et al., 2004; Gothard et al .,2010). Patients with bilateral lymphedema were also excluded because the contralateral normal limb was needed to predicate percentage of lymphedema (Omar, Ebid, & El Morsy, 2011; Carati, Anderson, Gannon, & Piller, 2003; Teas et al., 2004; Gothard et al., 2010).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Seventy four females were recruited from the surgical department at National Cancer Institute, Cairo, Egypt, between September 2010 and May 2012.
All patients had been undergoing breast cancer surgeries.
The patients met with the evaluator therapist who conducted the assessments. The evaluator therapist was blinded to the group assignment. Following their assessments, the patients were randomly assigned to ozone or control groups. Therefore, neither patients nor the evaluator therapist knew who was in which group. central randmization uisng computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
All subjects were participated in single blinded, randomized, control trial. We generated a computerized random number list and the subject allocation sequence was created from the list.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis
To avoid a type II error, we aimed to recruit 60 participants, giving 80% power, at a = 0.05 and effect size =0.35 to detect a 14.4% mean difference in lymphedema between the two groups (Omar, Ebid, & El Morsy, 2011). Then we generated a computerized random number list, and the subject allocation sequence was created from the list.

Statistical analyses of the differences in limb volume, skin and subcutis thicknesses were performed using Statistical Package for the Social Sciences Version 17.0 (SPSS Inc., Chicago, IL, USA). Parametric tests were used to summarize and analyze the primary and secondary outcomes since the data were normally distributed. P-value <0.05 was considered to be statistically significant.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 4950 0
Egypt
State/province [1] 4950 0

Funding & Sponsors
Funding source category [1] 286942 0
Self funded/Unfunded
Name [1] 286942 0
Address [1] 286942 0
Country [1] 286942 0
Primary sponsor type
Individual
Name
Intsar S. Waked,
Address
Faculty of Physical Therapy, Physical Therapy Department for Surgery, 7 Ahmad Alzayat St., Bain El-sarayat, Giza, Egypt.
Postal Code: 12612
Country
Egypt
Secondary sponsor category [1] 285727 0
Individual
Name [1] 285727 0
Mohammed Taher Ahmed Omar
Address [1] 285727 0
Faculty of Physical Therapy, Physical Therapy Department for Surgery, 7 Ahmad Alzayat St., Bain El-sarayat, Giza, Egypt.
Postal Code: 12612
Country [1] 285727 0
Egypt
Other collaborator category [1] 277330 0
Individual
Name [1] 277330 0
Samah H. Nagib
Address [1] 277330 0
Cairo University, Faculty of Physical Therapy, Physical Therapy Department for Surgery, 7 Ahmad Alzayat St., Bain El-sarayat, Giza, Egypt.
Postal Code: 12612
Country [1] 277330 0
Egypt

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288994 0
postgraduate ethics committee, faculty of physical therapy, cairo university
Ethics committee address [1] 288994 0
Cairo University, Faculty of Physical Therapy, Physical Therapy Department for Surgery, 7 Ahmad Alzayat St., Bain El-sarayat, Giza, Egypt. Postal Code: 12612
Ethics committee country [1] 288994 0
Egypt
Date submitted for ethics approval [1] 288994 0
02/02/2010
Approval date [1] 288994 0
25/03/2010
Ethics approval number [1] 288994 0
10099PCEC

Summary
Brief summary
Current treatment for breast cancer related lymphedema (BCRL) is controversial (Anonymous, 2009). Several therapeutic options have been provided, such as compression garments or bandaging, manual lymphatic drainage (MLD), complex decongestive therapy (CDT), pneumatic compression pump, exercises, (Partsch, Stout, & Forner-Cordero, 2010; Andersen, Hojris, Erlandsen, & Andersen, 2000; Badger, Peacock, & Mortimer, 2000; Guerreiro, Oliani, & Pereira, 2010). More recently low level laser therapy has been used, however, the results of these therapies vary widely and inconsistent (Dirican.et al, 2010; Omar, Ebid, & El Morsy, 2011; Carati, Anderson, Gannon, & Piller, 2003).


Recent research suggests that lymphedema might be improved by high-pressure oxygen therapy. The use of oxygen might stimulate the growth of new lymphatic channels and reduction of the scar tissues surrounding existing lymphatic channels leading to reduction of limb volume (Teas et al., 2004; Gothard et al., 2010).
Ozone is a naturally-occurring configuration of three oxygen atoms best known for its protective role in the earth's ecological harmony, possesses unique properties, which are being defined and applied to biological systems as well as to clinical practice. As a molecule containing a large excess of energy, ozone manifests bactericidal, virucidal and fungicidal actions that might make it a treatment of choice in certain conditions and an adjunctive treatment in others (Sunnen ., 2005; Young & Setlow., 2004). Therefore, the purpose of this prospective, single-blinded, randomized controlled trial was to investigate the efficacy of ozone therapy in the management of BCRL among women with breast cancer therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38694 0
Dr Intsar S. Waked
Address 38694 0
Cairo University, Faculty of Physical Therapy, Physical Therapy Department for Surgery, 7 Ahmad Alzayat St., Bain El-sarayat, Giza, Egypt. Postal Code: 12612
Country 38694 0
Egypt
Phone 38694 0
+966542115404
Fax 38694 0
Email 38694 0
momarar@cu.edu.eg
Contact person for public queries
Name 38695 0
A/Prof Mohammed Taher Ahmed Omar
Address 38695 0
Cairo University, Faculty of Physical Therapy, Physical Therapy Department for Surgery, 7 Ahmad Alzayat St., Bain El-sarayat, Giza, Egypt.Postal Code: 12612
Country 38695 0
Egypt
Phone 38695 0
+966542115404
Fax 38695 0
Email 38695 0
momarar@cu.edu.eg
Contact person for scientific queries
Name 38696 0
A/Prof Mohammed Taher Ahmed Omar
Address 38696 0
Cairo University, Faculty of Physical Therapy, Physical Therapy Department for Surgery, 7 Ahmad Alzayat St., Bain El-sarayat, Giza, Egypt.Postal Code: 12612
Country 38696 0
Egypt
Phone 38696 0
+966542115404
Fax 38696 0
Email 38696 0
momarar@cu.edu.eg

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary