Clinical trial NCT04167085
Conditions: Epistaxis
Keywords: Epistaxis Hereditary Hemorrhagic Telangiectasia HHT Doxycycline Nosebleed
Sponsor: University of California, Los Angeles
Start date: 2017-12-18; Completion date: 2021-06-01
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this research study is to determine whether Doxycycline can be used to control nosebleeds (epistaxis) for patients with Hereditary Hemorrhagic Telangiectasia (HHT). Patients with HHT will be randomized to one of 2 study arms: Doxycycline or Placebo for a period of 2 months followed by a 1-month washout period before switching treatments for a further 2 months period. Observation and evaluation will continue for a period of one month after treatment is completed.

Detailed description:
This study will analyze the effect of doxycycline on nosebleeds in hereditary hemorrhagic telangiectasia (HHT), a rare and debilitating medical condition. Patients with HHT have a variety of vascular abnormalities, including changes in their nasal vasculature that result in chronic, severe nosebleeds. These nosebleeds have been shown to significantly reduce the quality of life in HHT and can be severe enough to require emergent blood transfusion. Current therapies to control nosebleeds in HHT, which include both medications and surgical treatments, are inconsistently effective and associated with a variety of problematic side effects and complications.

Doxycycline is a common, FDA-approved antibiotic medication that has been used by physicians for decades. It is a safe medication that can be used on an outpatient basis for extended periods of time with minimal side effects. Recent research has shown that doxycycline is a potent inhibitor of angiogenesis, the process of new blood vessel development. Since the vascular abnormalities in HHT form due to uncontrolled angiogenesis, it follows that doxycycline may have potential in treating HHT. A growing body of research demonstrates the efficacy of doxycycline in treating a variety of vascular conditions, including cancer of the breast, duodenum, liver prostate, and lung. Our trial will be the first to analyze the efficacy of doxycycline in treating HHT epistaxis.

This a randomized, double-blind, crossover study design. Each patient will take both placebo and doxycycline. Since this is a cross-over study, half the participants will start out with taking placebo and half start with doxycyline and then switch halfway through. After a baseline observation period, participants will be given doxycycline at 100 mg twice a day, or an identical-appearing placebo, for a period of three months. Each month they will be seen be a physician, who will take a detailed clinical history and perform a physical examination. Further, each month the patient will have blood testing to assess blood loss, and fill out scientifically validated surveys to assess quality of life and the severity of bleeding. Following this three month treatment period, participants will be observed for one additional month, with one additional blood test and clinical assessment performed after this month.

Arms: arm 1: Doxycycline for a period of 2 months followed by a 1-month washout period, and then placebo for a further 2 months period followed by a 1-month washout period. arm 2: Placebo for a period of 2 months followed by a 1-month washout period, and then Doxycycline for a further 2 months period followed by a 1-month washout period.
Interventions: intervention 1: Doxycycline intervention 2: Placebo
Intervention descriptions: intervention 1: Doxycycline, 100 mg twice a day for 2 months intervention 2: Matching placebo, twice a day for 2 months

Protocol documents:
Prot_SAP_000.pdf: 
UCLA Medical Center 
                     Confidential 
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Research Study Proposal 
 
This document is property of Justin McWilliams, MD/UCLA Medical Center and shall not be reproduced, 
distributed, disclosed, or used for manufacture or sale of apparatus without the expressed written 
consent of the University of California, Los Angeles. 
 
 
 
 
NCT04167085 
March 20, 2020 
 
Research Study Protocol v1 
 
 
 
Study Title:  
NOrth american Study for the Treatment of Recurrent epIstaxis 
with doxycycLine: The NOSTRIL Trial 
 
 
Study Design:                      
Prospective, Randomized (1:1), Double blind placebo controlled 
crossover study 
 
 
 
Proposed In-life Start: 
 07-01-2017 
 
 
Funding Source:                        Department of Radiology (Exploratory Grant) 
 
 
 
Principal Investigator: 
Justin McWilliams, MD 
 
 
       
                                                     310-267-8773  
jumcwilliams@mednet.ucla.edu 
 
 
 
 
 
 
 
 
 


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consent of the University of California, Los Angeles. 
 
 
 
1. Introduction 
 
a. Background and significance 
 
Hereditary Hemorrhagic Telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an 
autosomal dominant disorder characterized by multi-systemic vascular abnormalities. The condition 
is associated with fragile telangiectasias and arteriovenous malformations (AVMs), which can affect 
the lungs, liver, brain, and mucosal surfaces. These abnormalities can result in severe and potentially 
fatal complications, including stroke, brain abscess, heart failure, and pulmonary hypertension. 
Although it is a rare condition, there is a large affected population with an estimated incidence of 1 in 
5000-8000 people. 
 
The most common manifestation of HHT is recurrent epistaxis, which often develops before age 10 
and is eventually seen in nearly all HHT patients. Epistaxis results from telangiectasias of the nasal 
mucosa, which are fragile and can spontaneously rupture. Complications related to epistaxis in HHT 
include chronic iron deficiency anemia, severe blood loss requiring emergent blood transfusion, and 
in some cases death. Data also shows that epistaxis is a significant contributor to decreased quality of 
life in HHT, with HHT patients identifying epistaxis as a priority issue for HHT research. Current 
therapies for HHT epistaxis include both medical and surgical interventions. Medications that may 
have benefit include estrogens, progestogens, and antifibrinolytics such as tranexamic acid. These 
medications, however, are associated with concerning and poorly characterized side effects and their 
benefit is generally inconsistent. Relevant procedural interventions include laser cauterization, septal 
dermoplasty, embolization, and nasal closure. Disadvantages of these approaches include their 
invasive nature and associated risks, as well as a generally temporary benefit. 
 
Anti-angiogenic agents are being increasingly used to control bleeding in HHT patients, since the 
fundamental problem in HHT is abnormal angiogenesis. Reduced activation of TGF-β and increased 
levels of vascular endothelial growth factor (VEGF) results in unregulated angiogenesis and leads to 
formation of disordered and fragile blood vessels on the mucosal surfaces, particularly in the nose 
and gastrointestinal tract, which are prone to spontaneous and recurrent bleeding (1). Anti-
angiogenic agents such as bevacizumab and thalidomide have been used with great success to reduce 
the formation of these abnormal vessels and reduce bleeding in HHT patients (2-7). Therapeutic effect 
has been seen even at low doses of these agents, suggesting that the telangiectasias of HHT may be 
particularly sensitive to anti-angiogenic agents (8,9). However, the existing anti-angiogenic therapies 
are expensive, difficult to administer, and hard to tolerate due to frequent side effects. There is great 
need for a drug which can replicate these anti-angiogenic effects but which is well-tolerated, orally-
administered, inexpensive and readily available. 
            
Data suggests that doxycycline, a common medication used for decades in the treatment of bacterial 
infections, may have potential in the treatment of HHT epistaxis. Recent studies reveal that 
doxycycline has potent anti-angiogenic properties, inhibiting matrix metalloproteinases (MMPs) 
which function to allow endothelial cells to migrate during angiogenesis. These anti-angiogenic 
properties have been demonstrated in multiple in-vivo and in-vitro studies (10-14). Doxycycline seems 
to effect anti-angiogenesis not only by matrix metalloproteinase inhibition, but also by reducing the 


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distributed, disclosed, or used for manufacture or sale of apparatus without the expressed written 
consent of the University of California, Los Angeles. 
 
effect of VEGF (15) and inhibiting pro-angiogenic macrophages (16). Multiple in-vitro studies have 
demonstrated suppression of tumor growth and vascularization in cell lines exposed to doxycycline, 
including lung, cervical, ovarian, pancreatic, and colorectal cancers (17-21). 
            
The potential of doxycycline to suppress angiogenesis and reduce nosebleeds has been previously 
recognized and studied in a pilot study (22). A retrospective analysis of seven HHT patients treated 
with oral doxycycline demonstrated that epistaxis severity score (ESS) significantly decreased with 
treatment, from a pre-treatment ESS of 4.9 to a post-treatment ESS of 2.6. This almost 50% reduction 
in nosebleed severity underscores the anti-angiogenic properties of doxycycline and supports the 
potential of this therapy in HHT.  
 
The NOSTRIL study will be the first prospective, randomized trial to assess the control of epistaxis in 
HHT with prophylactic doxycycline. This therapy has the potential to dramatically improve the health 
and quality of life of patients with HHT. 
 
2. Objectives and Specific Aims 
The objective of this study is to determine whether prophylactic oral doxycycline is effective in 
reducing epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT).  
 
We will perform a comparative, blinded, randomized (1:1) controlled trial to treat HHT patients with 
nosebleeds with doxycycline versus placebo. This project has the following specific aims: 
 
1. Determine the effect of doxycycline treatment versus placebo on the frequency, duration, and 
severity of nasal bleeding in HHT. Bleeding will be quantified in a systematic manner using the 
Epistaxis Severity Score (ESS), a validated and objective tool for the assessment of epistaxis severity. 
We will further quantify bleeding using a patient nosebleed diary including frequency, duration and 
severity of nosebleeds. 
 
2. Determine the effect of doxycycline treatment versus placebo on quality of life in HHT. Data has 
shown that recurrent epistaxis significantly reduces quality of life in HHT, and HHT patients have 
identified epistaxis as a key focus for future research in the treatment of the disease. We will 
evaluate quality of life using the objective, validated Short Form-12 (SF-12) Health Status 
Questionnaire.  
 
3. Determine the effect of doxycycline treatment versus placebo on objective laboratory measures 
of bleeding, including hematocrit, hemoglobin, and ferritin. 
 
4. Determine the effect of doxycycline treatment versus placebo on the need for transfusion in HHT. 
Transfusion is used in cases of severe, life-threatening bleeding, and in many cases is required in 
HHT-related epistaxis. We will compare the quantitative units of packed red blood cells (PRBCs) 
required with and without doxycycline therapy. 
 
Hypothesis: Treatment with doxycycline results in significant improvement in HHT epistaxis 
compared to placebo, which is manifested by reduced clinical bleeding, better quality of life, 
improvement in objective laboratory values such as hemoglobin levels, and reduced need for blood 
transfusion. 


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3. Study Design and Dose Rationale 
 
a. Study Design Rationale 
A randomized (1:1), prospective, cross-over design will be used. This guarantees that all participants 
will receive treatment with the treatment drug, which is important since all patients enrolled will have 
significant epistaxis and desire treatment. An identical design was used in a previous study of epistaxis 
reduction in HHT patients (23).  
 
A one-month wash-out period between placebo and treatment drug was selected based on 
doxycycline pharmacokinetics and mucosa turnover rate. Doxycycline is almost completely absorbed 
orally with bioavailability of 95% and a time to peak concentration of about 3 hours. The half-life of 
the drug is about 14 hours, with elimination in both the urine and stool. Thus, the drug will be almost 
completely absent one week after the last dose (12 half-lives). The nasal mucosa, which could be 
affected by the drug, regenerates approximately every 5 days (24). Thus the biologic effect of the drug 
should be virtually absent by 12 days after the last dose. To ensure complete clearance of the drug and 
its effects between therapy and placebo, an additional two weeks were added, making a total one-
month wash-out period. 
 
Subjects who cannot present in person to the clinic due to the COVID-19 virus will conduct the follow-
up visit over the phone. 
 
Based on preliminary data (14) the average epistaxis severity score (ESS) for the patients we will recruit 
is 4.9 ± 2.2. The preliminary study found that doxycycline treatment reduced the ESS by an average of 
2.4 ± 1.2 points.  Thus, a sample size of 20 patients from the cross over design will achieve 90% power 
to test the mean differences in ESS between doxycycline and placebo at alpha of 5% using a two-sided 
t-test. To consider the possible dropout or missing (approximately 10% rate), a total sample size of 22 
patients will be randomized. This was the same sample size used in the previous cross-over trial of a 
different medication in HHT patients with epistaxis (23). 
 
b. Dose Rationale 
The dose of doxycycline used in this study will be 100 mg PO BID. This is the standard dose of the drug 
for anti-bacterial use, and thus the pharmacokinetics and drug safety profile are best known at this 
dose. The preliminary trial of doxycycline in HHT patients used the same dose (14), as did several 
clinical trials of doxycycline for treatment of cancer and lymphangioleiomyomatosis (24,25). 
 
4. Study procedures 
This trial will be performed with UCLA Institutional Review Board approval and in accordance with the 
Declaration of Helsinki, with all patients providing written informed consent. 
 
a. Study Design: 
i. 
This is a single-center, prospective, randomized (1:1), controlled, cross over, double-
blinded study 
ii. 
Total N = 22 Patients 
iii. 
The following information will be collected during the study: 
1- Demographic information 


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2- Medical history 
3- Physical Examination 
4- Concomitant medication 
5- Adverse events 
6- Vital signs  
7- SF-12 quality of life questionnaire 
8- ESS score 
9- Labs 
 
iv. 
Eligible patients will have a diagnosis of definite HHT by the Curacao criteria or a positive 
DNA test for HHT (relevant mutation in the genes coding for SMAD-4, ALK-1, or endoglin). 
Other inclusion criteria include age 18 or older, avoidance of other experimental 
therapies during the trial, and significant epistaxis (minimum of 3 bleeding episodes per 
week, total duration of nosebleeds at least 15 minutes per week). Female patients with 
childbearing potential will require a negative pregnancy test on Day 1 of the trial and at 
the Crossover visit. Female patients with childbearing potential will also agree to use birth 
control during the study from Day 1 of the trial (First and Second arm) and for 28 days 
following cessation of the study medications (Placebo and Doxycyclyne).  Patients will also 
be excluded if they have used certain medications within 14 days prior to the study, 
including barbiturates, tegretol, dilantin, warfarin, isotretinoin, and a variety of other 
medications that are contra-indicated with doxycycline use. 
 
v. 
Consented subjects will be randomized and blinded to the study medications. Subjects 
will be randomized to either the Doxycycline arm (100mg PO BID) or to the placebo arm 
(2 placebo pills/day). After randomization, subjects will have 15 days to 1 month run in 
period to establish baseline characteristics (bleeding) prior to treatment initiation. As this 
is a crossover study, subjects will start with one treatment for 2 months followed by a 1 
month washout period and then switch to the second treatment for another 2 months 
and a 1 month follow-up visit. 
 
vi. 
Both Doxycycline and placebo drugs will be dispensed by the Ronald Reagan UCLA 
Medical Center (RRUMC) investigational pharmacy. The exploratory grant is covering for 
the cost of the drugs. 
 
 
b. Outcomes 
The primary outcome measures will be the frequency and duration of epistaxis as determined by a 
nosebleed diary and the Epistaxis Severity Scale (ESS), a validated objective measure of epistaxis 
severity. The ESS metric has been recommended for the evaluation of new epistaxis therapies. There 
will also be a number of secondary measures. First, we will evaluate patient quality of life using the 
objective Short Form-12 (SF-12) Health Status Questionnaire. Laboratory markers of bleeding will 
represent an additional secondary outcome measure and include ferritin, hemoglobin, hematocrit 
and MMP-9. To evaluate for severe bleeding requiring transfusion, we will quantify the units of packed 
red blood cells (PRBCs) transfused over each one-month period of observation. Finally, we will 
evaluate for treatment failure, including need for nasal surgery or other epistaxis treatments. 
 


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c. Inclusion/Exclusion Criteria 
 
i. 
Inclusion Criteria 
- Age 18 and older 
- Diagnosis of definite HHT by the Curacao criteria or positive genetic test for HHT 
- Epistaxis severity during the observation month is at least moderate by Epistaxis Severity 
Score (ESS) evaluation, a validated objective index of bleeding severity 
- Female patients with childbearing potential will require a negative pregnancy test on 
the first day of the trial and at the crossover visit. They will also agree to use birth control 
during the study medication period (placebo and Doxycycline) and for 28 days post study 
medication intake. This is due to the fact that doxycycline is a Pregnancy Category D 
medication and since this is a double blinded study, patients need to be on birth control 
on both arms 
 
ii.  
Exclusion Criteria 
 
 - Patients will be disqualified for use of certain medications within 14 days prior to the 
study, including barbiturates, tegretol, dilantin, warfarin, isotretinoin, and several other 
medications that are contra-indicated with doxycycline use. 
 
5. Monitoring and Safety Mechanisms 
a. The study will follow the OHRPP Data Security in Research guidance and procedures for 
data security. The study data will be coded and no personal information will be recorded. 
b. Patient safety monitoring will be performed by the principal investigator. Any events or 
unforeseen complications during and after the treatment period will be promptly 
assessed and any required intervention will be performed to minimize any compromise 
to patient care and safety. 
 
6. Statistical Analysis and Method of Data Analysis 
All data will be summarized with descriptive statists (number of subjects, mean, standard deviation, 
minimum, median, and maximum) for continuous endpoints and frequency and percentage for 
categorical endpoints. 
 
The differences between outcome measures in the doxycycline group versus the placebo group will 
be contrasted using Student’s t-test for each of the primary and secondary outcome measures. If the 
outcome measurements do not meet the normality assumption even after a transformation, non-
parametric approach of Wilcoxon sign-rank tests can be used to test the differences between 
doxycycline and placebo. Although we will have enough washout time before cross over to other 
treatment arm, we can test the effects of sequence and carryover in a model. 
 
 
 
 
 
 
 
 


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consent of the University of California, Los Angeles. 
 
 
 
 
 
 
 
 
 
 
References 
 
1. Ardelean DS, Letarte M. Anti-angiogenic therapeutic strategies in hereditary hemorrhagic telangiectasia. 
Front Genet. 2015 Feb 11;6:35. 
2. Chavan A, Schumann-Binarsch S, Luthe L, Nickau B, Elsässer A, Kühnel T, Geisthoff U, Köhne H. Systemic 
therapy with bevacizumab in patients with hereditary hemorrhagic telangiectasia (HHT). Vasa. 2013 
Mar;42(2):106-10. 
3. Epperla N, Hocking W. Blessing for the bleeder: bevacizumab in hereditary hemorrhagic telangiectasia. Clin 
Med Res. 2015 Mar;13(1):32-5. 
4. Fleagle JM, Bobba RK, Kardinal CG, Freter CE. Iron deficiency anemia related to hereditary hemorrhagic 
telangiectasia: response to treatment with bevacizumab. Am J Med Sci. 2012 Mar;343(3):249-51. 
5. Fang J, Chen X, Zhu B, Ye H, Zhang W, Guan J, Su K. Thalidomide for Epistaxis in Patients with Hereditary 
Hemorrhagic Telangiectasia: A Preliminary Study. Otolaryngol Head Neck Surg. 2017 Apr 
1:194599817700573. 
6. Franchini M, Frattini F, Crestani S, Bonfanti C. Novel treatments for epistaxis in hereditary hemorrhagic 
telangiectasia: a systematic review of the clinical experience with thalidomide. J Thromb Thrombolysis. 
2013 Oct;36(3):355-7. 
7. Sehl ME, M Gruber T, McWilliams JP, Marder VJ. Successful management of chronic gastrointestinal 
hemorrhage using bevacizumab in the setting of hereditary hemorrhagic telangiectasia. Am J Hematol. 2015 
Jun;90(6):561-3. 
8. Thompson AB, Ross DA, Berard P, Figueroa-Bodine J, Livada N, Richer SL. Very low dose bevacizumab for 
the treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia. Allergy Rhinol 
(Providence). 2014 Jul;5(2):91-5. 
9. Wee JW, Jeon YW, Eun JY, Kim HJ, Bae SB, Lee KT. Hereditary hemorrhagic telangiectasia treated with low 
dose intravenous bevacizumab. Blood Res. 2014 Sep;49(3):192-5. 
10. Cox CA, Amaral J, Salloum R, Guedez L, Reid TW, Jaworski C, John-Aryankalayil M, Freedman KA, Campos 
MM, Martinez A, Becerra SP, Carper DA. Doxycycline's effect on ocular angiogenesis: an in vivo analysis. 
Ophthalmology. 2010 Sep;117(9):1782-91. 
11. Richardson M, Wong D, Lacroix S, Stanisz J, Singh G. Inhibition by doxycycline of angiogenesis in the 
chicken chorioallantoic membrane (CAM). Cancer Chemother Pharmacol. 2005 Jul;56(1):1-9. 
12. Meng J, Sun B, Zhao X, Zhang D, Zhao X, Gu Q, Dong X, Zhao N, Liu P, Liu Y. Doxycycline as an inhibitor of 
the epithelial-to-mesenchymal transition and vasculogenic mimicry in hepatocellular carcinoma. Mol 
Cancer Ther. 2014 Dec;13(12):3107-22. 
13. Wang SQ, Zhao BX, Liu Y, Wang YT, Liang QY, Cai Y, Zhang YQ, Yang JH, Song ZH, Li GF. New application of 
an old drug: Antitumor activity and mechanisms of doxycycline in small cell lung cancer. Int J Oncol. 2016 
Apr;48(4):1353-60. 
14. Huie M, Oettel K, Van Ummersen L, Kim KM, Zhang Y, Staab MJ, Horvath D, Marnocha R, Douglas J, 
Drezen A, Alberti D, Wilding G. Phase II study of interferon-alpha and doxycycline for advanced renal cell 
carcinoma. Invest New Drugs. 2006 May;24(3):255-60. 


UCLA Medical Center 
                     Confidential 
     Page 8 of 8 
Research Study Proposal 
 
This document is property of Justin McWilliams, MD/UCLA Medical Center and shall not be reproduced, 
distributed, disclosed, or used for manufacture or sale of apparatus without the expressed written 
consent of the University of California, Los Angeles. 
 
15. Su W, Li Z, Li F, Chen X, Wan Q, Liang D. Doxycycline-mediated inhibition of corneal angiogenesis: an 
MMP-independent mechanism. Invest Ophthalmol Vis Sci. 2013 Jan 28;54(1):783-8. 
16. He L, Marneros AG. Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and 
subsequent neovascularization. J Biol Chem. 2014 Mar 21;289(12):8019-28. 
17. Zhao Y, Wang X, Li L, Li C. Doxycycline inhibits proliferation and induces apoptosis of both human 
papillomavirus positive and negative cervical cancer cell lines. Can J Physiol Pharmacol. 2016 
May;94(5):526-33. 
18. Qin Y, Zhang Q, Lee S, Zhong WL, Liu YR, Liu HJ, Zhao D, Chen S, Xiao T, Meng J, Jing XS, Wang J, Sun B, Dai 
TT, Yang C, Sun T, Zhou HG. Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the 
proliferation and metastasis of lung cancer cells. Oncotarget. 2015 Dec 1;6(38):40667-79. 
19. Wu W, Yu LH, Ma B, Xu MJ. The inhibitory effect of doxycycline on cisplatin-sensitive and -resistant 
epithelial ovarian cancer. PLoS One.  2014 Mar 5;9(3):e89841. 
20. Son K, Fujioka S, Iida T, Furukawa K, Fujita T, Yamada H, Chiao PJ, Yanaga K. Doxycycline induces apoptosis 
in PANC-1 pancreatic cancer cells. Anticancer Res. 2009 Oct;29(10):3995-4003. 
21. Sagar J, Sales K, Dijk S, Taanman J, Seifalian A, Winslet M. Does doxycycline work in synergy with cisplatin 
and oxaliplatin in colorectal cancer? World J Surg Oncol. 2009 Jan 6;7:2. 
22. Meek M, Womble P, Jordan A, Kanaan A, Meek J. Oral doxycycline for the treatment of epistaxis in patients 
with hereditary hemorrhagic telangiectasia. Angiogenesis. 2015; 18:530. 
23. Geisthoff UW, Seyfert UT, Kübler M, Bieg B, Plinkert PK, König J. Treatment of epistaxis in hereditary 
hemorrhagic telangiectasia with tranexamic acid – a double-blind placebo-controlled cross-over phase IIIB 
study. Thromb Res. 2014 Sep;134(3):565-71. 
24. Ohashi Y, Nakai Y, Ikeoka H, Furuya H. Regeneration of nasal mucosa following mechanical injury. Acta 
Otolaryngol Suppl. 1991;486:193-201. 
25. Han JJ, Kim TM, Jeon YK, Kim MK, Khwarg SI, Kim CW, Kim IH, Heo DS. Long-term outcomes of first-line 
treatment with doxycycline in patients with previously untreated ocular adnexal marginal zone B cell 
lymphoma. Ann Hematol. 2015 Apr;94(4):575-81. 
26. Chang WY, Cane JL, Kumaran M, Lewis S, Tattersfield AE, Johnson SR. A 2-year randomised placebo-
controlled trial of doxycycline for lymphangioleiomyomatosis. Eur Respir J. 2014 Apr;43(4):1114-23.